COSMIC v59 Release

This latest release of COSMIC includes full mutation spectra across three new cancer genes and 9 new gene fusions. Also included are updates from the latest TCGA and ICGC releases, together with 4 recent whole-genome publications.

Genes with fully curated mutation spectra.

SRSF2, U2AF1, ZRSR2
In addition to SF3B1, somatic mutations have been identified in other genes coding for components of the splicing machinery responsible for the processing of pre-mRNA to mature RNA. SRSF2, U2AF1 and ZRSR2 are mutated in haematopoietic neoplasms where there's further evidence for an association between clinical phenotype and the different splice gene mutations. Mutated SRSF2 is more frequently associated with leukaemic transformation and has a negative prognostic impact. For SRSF2 the recurrent mutations cluster at P95, while for U2AF1 the mutations cluster at 2 hotspots at S34 and Q157. ZRSR2 mutations are least frequent.

Curated fusion gene pairs:

YWHAE-FAM22A, YWHAE-FAM22B
Recurrent fusions of YWHAE and one of two FAM22 family members (FAM22A, FAM22B) have been identified as specific to high-grade endometrial stromal sarcoma (ESS), a clinically aggressive form of uterine sarcoma and distinct from the classic JAZF1-rearranged ESS. YWHAE encodes a member of the 14-3-3 protein family which plays a role in various signal transduction pathways and YWHAE-FAM22 fusions maintain a structurally and functionally intact YWHAE protein-binding domain. Identical fusions involving YWHAE-FAM22 have also been identified in clear cell sarcoma of kidney.

KIF5B-RET and CCDC6-RET
Fusions involving the kinesin family 5B gene and RET have been found recurrently in lung adenocarcinomas. Several transcript variants have been identified in which the KIF5B portion differs, but all retain the KIF5B coiled-coil domain that mediates homodimerization and all retain the full RET kinase domain. An additional RET fusion, involving CCDC6, has also been identified in lung adenocarcinoma.

EZR-ROS1, LRIG3-ROS1, SDC4-ROS1 and TPM3-ROS1
Four new fusion partners for ROS1, a receptor tyrosine kinase, have been found in non-small cell lung cancer, specifically adenocarcinoma. All of the breakpoints in ROS1 enable the resulting fusion to retain the ROS1 kinase domain and in the SDC4-ROS1 fusion, with a breakpoint at exon 32, the ROS1 transmembrane domain is also retained.

C2orf44-ALK
A novel ALK fusion involving C2orf44 has been identified in colorectal cancer. C2orf44, containing a coiled-coil domain, fuses to the canonical ALK exon 20 recombination site.

Whole genome resequencing data:

TCGA
The TCGA recently released large mutation datasets on three cancer types, Rectal, Colorectal and AML. This data has been curated from the TCGA data portal.

ICGC
The March release of the ICGC DCC (version 8) included four major new datasets, on liver , paediatric brain and two independent sets of pancreatic cancers (QCMG, Aus), (OICR,Canada). This information has been curated from the ICGC data release portal.

CGP
The complete genome sequences of 21 breast tumours have allowed the elucidation of the mutational process moulding these tumours. This data has been curated from pre-publication datasets here.

Shah, et al. (2012). The clonal and mutational evolution spectrum of primary triple-negative breast cancers.Nature (epub, pre-publication).

Focus on Blood tumours

Ding, et al. (2012). Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481:506-10.

Graubert, et al. (2012). Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nature Genetics 44:53-7.

Yoshida, et al. (2011). Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478:64-9.

The following genes have been updated in this release:

ABL1, ACVR1B, AKT1, ALK, APC, ARID1A, ASXL1, ATM, ATRX, AXIN1, BAP1, BRAF, BRCA1, BRCA2, CARD11, CBL, CDC73, CDH1, CDKN2A, CEBPA, CREBBP, CRLF2, CSF1R, CTNNA1, CTNNB1, CYLD, DAXX, DNMT3A, EGFR, EML4, EP300, ERBB2, EZH2, FAM123B, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, FOXL2, GATA1, GATA2, GATA3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, IKZF1, IL7R, JAK1, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MED12, MEN1, MET, MLH1, MLL2, MLL3, MPL, MSH2, MSH6, MYD88, NF1, NF2, NOTCH1, NOTCH2, NPM1, NRAS, NTRK3, PAX5, PDGFRA, PHOX2B, PIK3CA, PIK3R1, PPP2R1A, PRDM1, PRKAR1A, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SETD2, SF3B1, SMAD4, SMARCA4, SMARCB1, SMO, SRC, SRSF2, STK11, TET2, TNFAIP3, TP53, TSHR, U2AF1, VHL, WT1, ZRSR2

COSMIC v59 Total Statistics

Experiments	4799855
Tumours	713382
Samples	716988
Mutant Samples	282779
Mutations	298517
Unique Mutations	140641
Papers curated	13728
Genes	21425
Fusions	7732
Structural Variants	2882

Additional CGP resources:

The Cancer Gene Census, a listing of all genes known to be involved in cancer promotion

The Cancer Cell Line Project, defining key driver mutations in 800 common cancer cell lines

Genomics of Drug Sensitivity, Analysis of drug sensitivity data in human cancer cell lines.

CGP Copy Number Analysis in Cancer, examining tumours for gains or losses of genomic content

COSMIC v58 Release

Five new fusion gene pairs and one new cancer gene are curated in this 58th release of COSMIC, together with 6 recent genome-wide mutation screens.

Cancer Gene Census Update

Our curations have highlighted 13 new cancer genes KIF5B, C2orf44, CCDC6, SDC4, SLC34A2, EZR, LRIG3, H3F3A, DNM2, ECT2L, PHF6, WWTR1, CAMTA1, which have been added to the cancer gene census, bringing the total number of genes implicated in cancer to 487.

New curated genes:

AXIN1 functions as a scaffold protein regulating a variety of signalling pathways and biological functions. It is a key component of Wnt signalling binding to several of its members including APC, GSK3 and ??-catenin. Mutations in the AXIN1 gene, a tumour suppressor, lead to stabilization of ??-catenin and activation of target genes. AXIN1 mutations have been found in several cancers including colorectal, endometrial, prostate and hepatocellular as well as in hepatoblastoma and sporadic medulloblastoma. Mutations are found throughout the whole gene including the APC, GSK3 and ??-catenin binding domains. Biochemical and functional studies have shown that these mutations interfere with AXIN1 binding to GSK3 and interaction with two upstream activators Frat1 and DVL.

New Curated Gene Fusions:

HEY1-NCOA2, NUP107-LGR5
The novel, recurrent fusion HEY1-NCOA2 has been identified in mesenchymal chondrosarcoma as a potential molecular diagnostic marker. HEY1 is a downstream effector of Notch signalling and NCOA2 is a member of the p160 nuclear hormone receptor transcriptional co-activation family. In the HEY1-NCOA2 fusion, the N-terminal basic helix-loop-helix DNA-binding/protein dimerization domain from HEY1 is retained while the C-terminal portion is replaced by the NCOA2 ranscriptional activation domains AD1/CID and AD2. NUP107-LGR5 has also been identified, in dedifferentiated liposarcoma, as a novel but not recurrent translocation event.

SLC34A2-ROS1 and CD74-ROS1,
Two novel translocations have been identified in non small cell carcinoma of the lung. Fusion of ROS1, a receptor tyrosine kinase of the insulin receptor family, to the transmembrane solute carrier protein SLC34A2, where the N-terminal region of the latter is fused to the transmembrane region of ROS1, results in a protein with 2 transmembrane domains. Also fusion of ROS1 with CD74, a type II transmembrane protein with high affinity for the MIF immune cytokine, similarly results in a fusion protein with 2 transmembrane domains. Another ROS1 fusion, GOPC-ROS1, previously found in a glioblastoma cell line, has also been identified as a recurrent fusion in cholangiocarcinoma.

PAX8-PPARG
A subset of thyroid follicular carcinomas, and some follicular adenomas, has the PAX8-PPARG fusion. The DNA binding domains of PAX8, a thyroid cell transcription factor essential for the differentiation of follicular cells and the regulation of thyroid-specific genes, are fused to domains A-F of the peroxisome proliferator-activated receptor PPARG. Several splice variants have been identified in affected tumours with multiple transcripts expressed in some.

Systematic screen curations:

Yan XJ, et al. (2011). Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. NatGenet. 43;309-15

Pasqualucci L, et al. (2011). Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 43;830-7.

Quesada V, et al (2012). Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 44;47-52.

Jiao X, et al. (2012). Somatic mutations in the NOTCH, NF-KB, PIK3CA, and hedgehog pathways in human breast cancers. Genes Chromosomes Cancer.

The mutation data from exome sequencing of 10 Gastric tumours has been available in ICGC release 7 and is now incorporated into this release of COSMIC, here .

Stephens P and Tarpey P, et al. (2012).100 breast exomes have been sequenced by the CGP and are presented here as a pre publication release Nature (In Press)

The following genes have been updated in this release:

ABL1, ACVR1B, AKT1, ALK, APC, ARID1A, ASXL1, ATM, AXIN1, BAP1, BRAF, BRCA1, BRCA2, CARD11, CBL, CDC73, CDH1, CDKN2A, CEBPA, CREBBP, CSF1R, CTNNA1, CTNNB1, CYLD, DAXX, DNMT3A, EGFR, EML4, EP300, ERBB2, EZH2, FAM123B, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, FOXL2, GATA1, GATA3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, IKZF1, IL7R, JAK1, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MED12, MEN1, MET, MLH1, MLL2, MLL3, MPL, MSH2, MYD88, NF1, NF2, NOTCH1, NOTCH2, NPM1, NRAS, NTRK3, PAX5, PDGFRA, PIK3CA, PIK3R1, PPP2R1A, PRDM1, PRKAR1A, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SETD2, SF3B1, SMAD4, SMARCB1, SRC, STK11, TET2, TNFAIP3, TP53, TSHR, VHL, WT1

COSMIC v58 Total Statistics

Experiments	4720191
Tumours	698444
Samples	701963
Mutant Samples	233349
Mutations	242608
Unique Mutations	89393
Papers curated	13457
Genes	20948
Fusions	7633
Structural Variants	2752

Additional CGP resources:

The Cancer Gene Census, a listing of all genes known to be involved in cancer promotion

The Cancer Cell Line Project, defining key driver mutations in 800 common cancer cell lines

Genomics of Drug Sensitivity, Analysis of drug sensitivity data in human cancer cell lines.

CGP Copy Number Analysis in Cancer, examining tumours for gains or losses of genomic content

Census update

Four genes have been newly implicated in cancer : YWHAE, FAM22A and FAM22B translocations are associated with endometrial stromal carcinoma, whilst BCOR mutations are associated with Retinoblastoma, AML (Acute Myeloid Leukaemia) and APL (Acute promyelocytic leukemia). The census has been updated to reflect these new findings.

COSMIC v57 Release

Twelve new fusion gene pairs and one new cancer gene are curated in this 57th release of COSMIC, together with 8 recent genome-wide mutation screens.

Cancer Gene Census Update

Our curations have highlighted 6 new cancer genes FAM46C, FBXO11, HEY1, SRSF2, U2AF1, ZRSR2 which have been added to the cancer gene census, bringing the total number of genes implicated in cancer to 473.

New curated genes:

NFE2L2 encodes a transcription factor that induces expression of cytoprotective proteins upon oxidative stress. Oncogenic NFE2L2 mutations have been identified in lung, head-neck, oesophageal and skin cancers where they occur within or near 2 amino terminal motifs, DLG andETGE, both of which are important in the interaction of NFE2L2 with KEAP1, an E3 ubiquitin ligase involved in the negative regulation of NFE2L2 expression.

New Curated Gene Fusions:

EWSR1-NFATc2, EWSR1-SMARCA5
NFATc2, a transcription factor which is not a member of the ETS family and is involved in T-cell differentiation and immune response, is a recurrent novel 3' partner to EWSR1 in a histological variant of Ewings sarcoma. The resultant EWSR1-NFATc2 fusion protein lacks the COOH-terminal RNA binding domain of EWSR1, similar to other Ewing sarcoma-specific translocations, and the NH2-terminal transactivation domain and regulatory domain of NFATc2. Another novel 3' partner to EWSR1 in Ewings sarcoma is SMARCA5, a member of the WSTF-SNF2h chromatin-remodelling complex family of genes. The fusion protein, in addition to the SNYG N-terminal of EWSR1, contains 5 conserved domains and motifs of SMARCA5.

ZNF700-MAST1, TADA2A-MAST1, NFIX-MAST1, ARID1A-MAST2, GPBP1L1-MAST2, SEC16A-NOTCH1, NOTCH1-GABBR2,
Gene fusions involving members of the MAST kinase family have been identified in breast cancer at a frequency of 3-5%. All 5 MAST fusions encode contiguous ORFs, some of which retain the MAST serine-threonine kinase domain and all of which retain the PDZ domain and the 3' kinase-like domain. Additionally, gene fusions involving NOTCH1 have also been found in breast cancer where the exons that encode the Notch intracellular domain, responsible for inducing the transcriptional programme following Notch activation, are retained.

TCF12-NR4A3, TFG-NR4A3
TCF12 can replace EWSR1 or TAF15 as a fusion partner to NR4A3 in extraskeletal myxoid chondrosarcoma. The resulting fusion transcript encodes a protein in which the NH2-terminal domain of the basic helix-loop-helix protein TCF12 is fused to the whole NR4A3 protein. Also in extraskeletal myxoid chrondrosarcoma a fusion has been identified where TFG is a novel 5' partner to NR4A3.

DDX5-ETV4
In prostate carcinoma, DDX5 is an additional 5' partner to ETS transcription factor ETV4.

Systematic screen curations:

Focus on Melanoma

Prickett TD, et al. (2011). Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. NatGenet. [Epub ahead of print]

Wei X, et al. (2011). Analysis of the disintegrin-metalloproteinases family reveals ADAM29 and ADAM7 are often mutated in melanoma. Hum Mutat. 32:E2148-75.

Wei X, et al (2010). Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma. Mol Cancer Res.8:1513-25.

C??rdenas-Navia LI, et al. (2010). Novel somatic mutations in heterotrimeric G proteins in melanoma. Cancer Biol Ther. 10:33-7.

Cronin JC, et al (2009). Frequent mutations in the MITF pathway in melanoma. Pigment Cell Melanoma Res. 22:435-44.

Palavalli LH, et al. (2009). Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet.41:518-20.

Solomon DA, et al. (2008). Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma. Cancer Res. 68:10300-6.

Focus on Squamous Cell Carcinoma

Durinck S, et al. (2011). Temporal dissection of tumorigenesis in primary cancers. Cancer Discov. 1:137-143.

   (with related data from Wang NJ et al (2011). Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. PNAS 108:17761-6.)

The following genes have been updated in this release:

ABL1, AKT1, ALK, APC, ARID1A, ASXL1, ATM, BRAF, BRCA1, CARD11, CBL, CDC73, CDH1, CDKN2A, CREBBP, CTNNA1, CTNNB1, CYLD, DAXX, DNMT3A, EGFR, EML4, EP300, ERBB2, EZH2, FAM123B, FGFR3, FLT3, FOXL2, HRAS, IDH1, IDH2, IL7R, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MED12, MLH1, MLL3, MPL, MSH2, MSH6, MYD88, NF1, NF2, NFE2L2, NOTCH1, NOTCH2, NPM1, NRAS, PDGFRA, PIK3CA, PIK3R1, PRDM1, PRKAR1A, PTCH1, PTEN, PTPN11, RB1, RUNX1, SETD2, SF3B1, SMAD4, SMARCA4, SMARCB1, SMO, TET2, TNFAIP3, TP53, VHL, WT1

COSMIC v57 Total Statistics

Experiments	4671089
Tumours	683702
Samples	687082
Mutant Samples	217031
Mutations	224634
Unique Mutations	75109
Papers curated	13121
Genes	20259
Fusions	7428
Structural Variants	2752

Additional CGP resources:

The Cancer Gene Census, a listing of all genes known to be involved in cancer promotion

The Cancer Cell Line Project, defining key driver mutations in 800 common cancer cell lines

Genomics of Drug Sensitivity, Analysis of drug sensitivity data in human cancer cell lines.

CGP Copy Number Analysis in Cancer, examining tumours for gains or losses of genomic content

COSMIC v56 Release

Three new cancer genes together with 13 new fusion gene pairs and 7 recent genome-wide screens have been fully curated into COSMIC for this latest release.

Cancer Gene Census Update

Our curations have highlighted 4 new cancer genes IL7R, VTI1A, TCF7L2, NDRG1 which have been added to the cancer gene census, bringing the total number of genes implicated in cancer to 468.

New curated genes:

IL7R Interleukin-7 receptor alpha (IL7R) is required for normal lymphoid development and has been shown to carry somatic, heterozygous, gain of function mutations in 8- 10% of B and T cell leukaemias. To-date mutations have commonly fallen into 2 classes, S185C substitution in the extracellular domain (B-ALL) or in-frame insertions/deletions in the extracellular juxtamembrane transmembrane interface region (T- and B-ALL), the majority of which also introduce an unpaired cysteine residue. Biochemical and functional assays have demonstrated that the mutations are activating.

MED12 Oncogenic somatic mutations in MED12, an X chromosome gene encoding a subunit of the Mediator Complex, have been found in uterine leiomyomas (fibroids) with a frequency of 70%. Mutations are clustered in exon 2.

SF3B1, a gene encoding a core component of the RNA splicing machinery, is oncogenic in myelodysplastic syndromes (MDS), particularly those associated with increased ringed sideroblasts. With high mutation frequency and specificity, SF3B1 mutations are strongly implicated in the pathogenesis of these MDS subtypes. Recurrent SF3B1 mutations have also been identified in chronic lymphocytic leukaemia with higher frequency in chemorefractory cases.

New Curated Gene Fusions:

VTI1A-TCF7L2
Recurrent VTI1A-TCF7L2 fusions have been found in colorectal adenocarcinomas. VTI1A encodes a v-SNARE protein while CF7L2 encodes the transcription factor TCF4 which dimerizes with beta-catenin. The fusion results in the omission of the TCF4 beta-catenin-binding domain.

GOPC-ROS1
A fusion involving the amino-terminal portion of GOPC and the carboxy-terminal kinase domain of ROS1, a receptor tyrosine kinase, occurs in glioblastoma multiforme. The resulting fusion protein is a constitutively activated tyrosine kinase.

HNRNPA2B1-ETV1, SLC45A3-ETV1, ACSL3-ETV1,KLK2-ETV1,KLK2-ETV4,CANT1-ETV4,SLC45A3-ERG,NDRG1-ERG
In prostate carcinoma, minor novel 5' partners, apart from TMPRSS2, have been identified in recurrent fusions with ETS transcription factors ETV1, ETV4 and ERG.

SLC45A3-ELK4, SLC45A3-ETV5, TMPRSS2-ETV5
Both ELK4 and ETV5 have been identified as other ETS transcription factors involved as 3' partners in recurrent fusions in prostate carcinoma.

Systematic screen curations:

TCGA (2011). Integrated genomic analyses of ovarian carcinoma. Nature 474:609-15

Stransky et al (2011). The mutational landscape of head and neck squamous cell carcinoma. Science 333:1157-60

Li et al (2011). Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nature Genetics 43:828-9

Prickett et al (2009). Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4.Nature Genetics 41:1127-32

Bettegowda et al (2011).Mutations in CIC and FUBP1 contribute to human oligodendroglioma.Science 333:1453-5.

Papaemmanuil et al (2011).Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts.N Engl J Med. 365:1384-95

Malcovati et al (2011).Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferativeneoplasms. Blood (epub).

The following genes have been updated in this release:

ABL1, AKT1, ALK, APC, ARID1A, ASXL1, ATM, ATRX, BAP1, BRAF, BRCA1, BRCA2, CARD11, CBL, CDC73, CDH1, CDKN2A, CREBBP, CSF1R, CTNNA1, CTNNB1, CYLD, DAXX, DNMT3A, EGFR, EP300, ERBB2, EZH2, FAM123B, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GATA1, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, IKZF1, IL7R, JAK1, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MED12, MEN1, MET, MLL2, MLL3, MPL, MSH2, MSH6, MYD88, NF1, NF2, NOTCH1, NOTCH2, NPM1, NRAS, NTRK3, PAX5, PDGFRA, PIK3CA, PIK3R1, PPP2R1A, PRKAR1A, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SETD2, SF3B1, SMAD4, SMARCA4, SMARCB1, SMO, SRC, STK11, TET2, TNFAIP3, TP53, TSHR, WT1

COSMIC v56 Total Statistics

Experiments	4626046
Tumours	662467
Samples	665763
Mutant Samples	206711
Mutations	213615
Unique Mutations	67405
Papers curated	12818
Genes	20242
Fusions	7224
Structural Variants	2752

Additional CGP resources:

The Cancer Gene Census, a listing of all genes known to be involved in cancer promotion

The Cancer Cell Line Project, defining key driver mutations in 800 common cancer cell lines

Genomics of Drug Sensitivity, Analysis of drug sensitivity data in human cancer cell lines.

CGP Copy Number Analysis in Cancer, examining tumours for gains or losses of genomic content

COSMIC v55 Release

New curations include the tumour suppressor gene PRDM1, fusions of CRTC1/CRTC3-MAML2 and three new systematic screen publications. A new release of the Cancer Gene Census raises the number of known cancer genes to 464.

Cancer Gene Census Update

A number of genes have recently been implicated in oncogenesis and when this is confirmed, they are added to our Census of known cancer genes. The latest release details 464 known cancer genes, recently including SF3B1, ARID2, CCNE1, CDK12, FUBP1, XPO1, MED12.

New curated genes:

PRDM1 belongs to the PRDM gene family of transcriptional repressors characterized by DNA-binding Kruppel-type zinc fingers and the PR domain at the amino terminus. The encoded protein acts as a master regulator of B cell differentiation. PRDM1 has been identified as a tumour suppressor gene in the activated B cell-like subtype of diffuse large B cell lymphoma.

New Curated Gene Fusions:

CRTC1-MAML2 and CRTC3-MAML2,
CRTC1, a member of a family of CREB coactivators, is fused with MAML2, a gene belonging to a family of Mastermind-like genes, in mucoepidermoid carcinoma (MEC) of the salivary gland and lung. The recurrent fusion consistently has breakpoints in intron 1 of both gene partners resulting in the N terminal basic domain of MAML2 being replaced by the CREB-binding coiled-coil domain of CRTC1. The same CRTC1-MAML2 fusion is also found in a subset of Warthin's tumours of the salivary gland and in some hidradenomas. CRTC3 is occasionally an alternative fusion partner for MAML2 in MEC.

Systematic screen curations:

Agrawal et al (2011). Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science.333:1154-7

Wei et al (2011). Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nature Genetics. 43:442-6.

Zang et al (2010).Genetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing. Cancer Research 71:29-39.

The following genes have been updated in this release:

ABL1, ACVR1B, AKT1, ALK, APC, ARID1A, ASXL1, ATM, BAP1, BRAF, BRCA2, CARD11, CBL, CDC73, CDH1, CDKN2A, CEBPA, CREBBP, CSF1R, CTNNB1, DNMT3A, EGFR, EML4, EP300, ERBB2, ERG, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, FOXL2, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MET, MLL3, MPL, MSH6, NF1, NF2, NOTCH1, NOTCH2, NPM1, NRAS, NTRK3, PAX5, PDGFRA, PIK3CA, PIK3R1, PPP2R1A, PRDM1, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SMAD4, SMARCA4, SMARCB1, SMO, SRC, STK11, SUFU, TET2, TNFAIP3, TP53, TSHR, VHL, WT1

COSMIC v55 Total Statistics

Experiments	4577043
Tumours	639580
Samples	642744
Mutant Samples	186431
Mutations	192795
Unique Mutations	52524
Papers curated	12441
Genes	19885
Fusions	7062
Structural Variants	2752

Additional CGP resources:

The Cancer Gene Census, a listing of all genes known to be involved in cancer promotion

The Cancer Cell Line Project, defining key driver mutations in 800 common cancer cell lines

Genomics of Drug Sensitivity, Analysis of drug sensitivity data in human cancer cell lines.

CGP Copy Number Analysis in Cancer, examining tumours for gains or losses of genomic content

COSMIC v54 Release

COSMIC v54 Release

Five new cancer genes have received full curation of their mutation spectrum, together with seven new fusion gene pairs focusing on the zinc finger protein PLAG1. Four new systematic screens are included, covering a range of cancer phenotypes. This extensive literature curation brings the total number of publications in COSMIC to over 12,000.

New curated genes:

MLL2 and MLL3
MLL2 and MLL3, members of the mixed-lineage leukaemia family, have been confirmed as tumour suppressor genes in childhood medulloblastoma. They encode histone methyl-transferases that methylate key lysine residues of histone tails mediated through their SET domain activities. Both ofthese proteins are members of large transcriptional regulatory complexes involved in regulating chromatin structure and transcriptional co-activation.

NTRK3
NTRK3 encodes 1 of 3 high-affinity neurotrophin receptors that regulate growth, differentiation and apoptosis of neurons. It has been implicated in several tumour types including medulloblastoma, breast, colorectal, pancreas and large cell neuroendocrine tumours of the lung.

CREBBP and EP300
The histone acetyltransferase genes CREBBPand EP300 encode proteins which act as transcriptional co-activators in multiple signalling pathways. Both genes have been identified as tumour suppressors, with evidence of haploinsufficiency, in diffuse large B-cell lymphoma and follicular lymphoma where mutations affect the HAT coding domain. Mutations in CREBBP and EP300 are thus uncommon in epithelial cancers but have been found at high frequency in relapsed acute lymphoblastic leukaemia.

New Curated Gene Fusions:

CTNNB1-PLAG1, LIFR-PLAG1, CHCHD7-PLAG1, TCEA1-PLAG1, FGFR1-PLAG1,
A subset of pleomorphic adenomas of the salivary gland has PLAG1 fusions and 5 partner genes have so far been identified. Consistent breakpoints occur in the 5' non-coding region of PLAG1 leading to promoter swapping with the fusion partner gene. For 3 of the partners the breakpoint also occurs in the non-coding region while for TCEA1 and FGFR1 it interrupts the coding sequence. The PLAG1 protein contains an N-terminal zinc-finger DNA binding domain and a C-terminal transactivation domain.

HAS2-PLAG1 and COL1A2-PLAG1
PLAG1 fusions have also been detected in lipoblastomas where again the promoter region of the partner gene, in these cases HAS2 or COL1A2, is fused to the coding sequence of PLAG1.

Systematic screen curations:

Parsons DW, et al (2011). The genetic landscape of the childhood cancer medulloblastoma. Science 331:435-9.A large genome-wide candidate gene screen assessing childhood medulloblastoma, this study identified two new chromatin remodelling genes as cancer genes, MLL2 and MLL3.

Kan Z, et al (2010). Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466:869-73. This study examined 441 tumours from a variety of sites and morphologies, through over 1500 known or candidate cancer genes, defining roles for over 100 in oncogenesis.

Jones S, et al (2010). Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma. Science. 330:228-31 A whole-exome resequencing study of 8 ovarian clear cell carcinomas further implicates chromatin remodelling genes (PPP2R1A and ARID1A) in cancer.

Puente, et al (2011).Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 475:101-5 Full-genome resequencing of four Chronic Lymphocytic Leukaemia patients suggests significant roles for at least four known cancer genes (NOTCH1,XPO1, MYD88 and KLHL6). The data in this publication has been extended with extra annotations from their submission to the ICGC DCC (R5 release).

The following genes have been updated in this release:

ABL1, ACVR1B, AKT1, ALK, APC, ARID1A, ASXL1, ATM, BAP1, BRAF, BRCA1, BRCA2, CARD11, CBL, CDC73 , CDH1, CDKN2A, CEBPA, CREBBP, CRLF2, CSF1R, CTNNA1, CTNNB1, CYLD, DAXX, DNMT3A, EGFR, EML4, EP300, ERBB2, ERG, EZH2, FAM123B, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, FOXL2, GATA1, GATA2, GATA3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, IKZF1, JAK1, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MEN1, MET, MLH1, MLL2, MLL3, MPL, MSH2, MSH6, MYD88, NF1, NF2, NOTCH1, NOTCH2, NPM1, NRAS, NTRK3, PAX5, PDGFRA, PHOX2B, PIK3CA, PIK3R1, PPP2R1A, PRKAR1A, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SETD2, SMAD4, SMARCA4, SMARCB1, SMO, SOCS1, SRC, STK11, SUFU, TET2, TNFAIP3, TP53, TSHR, VHL, WT1

COSMIC v54 Total Statistics

Experiments	4531163
Tumours	619320
Samples	622464
Mutant Samples	177322
Mutations	183107
Unique Mutations	46615
Papers curated	12026
Genes	19737
Fusions	6365
Structural Variants	2752

Additional CGP resources:

The Cancer Gene Census, a listing of all genes known to be involved in cancer promotion

The Cancer Cell Line Project, defining key driver mutations in 800 common cancer cell lines

Genomics of Drug Sensitivity, Analysis of drug sensitivity data in human cancer cell lines.

CGP Copy Number Analysis in Cancer, examining tumours for gains or losses of genomic content

COSMIC v53 Release

COSMIC v53 release includes full curation of IKZF1, PIK3R1, PAX5 and 11 new gene fusion pairs.

This fifty third release of COSMIC brings the number of fully curated cancer genes to 98, together with a total of 81 curated fusion gene pairs. With the inclusion of 10 systematic screen publications, together with substantial output from the ICGC, TCGA and CGP studies, over 3 million curated gene screening experiments are now available in COSMIC, covering 19439 genes, with mutations identified on 11111 of these.

New curated genes:

IKZF1
IKZF1 encodes the zinc finger transcription regulator IKAROS involved in normal lymphoid development and is an important cancer gene in human B-cell progenitor acute lymphoblastic leukaemia (B-ALL). Whole gene deletions resulting in haploinsufficiency, focal somatic IKZF1 deletions (usually including exons encoding the DNA binding domain or regions immediately upstream of IKZF1) and somatic missense and frame shift mutations are observed in B-ALL. Focal deletions have been reported to result in the truncated transcripts that can encode dominant-negative proteins, as have some missense/frameshift mutations.

PIK3R1
PIK3R1 encodes p85alpha, the regulatory subunit of the phosphatidylinositol 3-kinase. It has an N-terminal SH3 domain, a domain homologous to the Rho GTPase-activating protein domain of the BCR gene product (BCR domain) and 2 SH2 domains that flank an intervening anti-parallel coiled-coil domain (iSH2) which mediates binding to p110alpha (PIK3CA) catalytic subunit, also a known cancer gene. PIK3R1 mutations have been identified in both colorectal and endometrial cancers where most are localized to the iSH2 domain.

PAX5
PAX5, a gene within the B-cell development pathway, encodes a transcription factor belonging to the family of paired-box domain transcription factors. Somatic mutations in PAX5, including partial and whole deletions, and point mutations which mostly cluster in the DNA-binding or transcriptional regulatory domains, have been identified in B-cell progenitor acute lymphoblastic leukaemia.

New Curated Gene Fusions:

BCR-JAK2, PCM1-JAK2, ETV6-JAK2, SSBP2-JAK2, SEC31A-JAK2, PAX5-JAK2
JAK2, JAK2 fusions involving multiple partner genes have been identified in haematological malignancies. Whereas the fusion proteins BCR-JAK2, ETV6-JAK2 and PAX5-JAK2 include the protein tyrosine kinase domain (JH1) of JAK2, PCM1-JAK2 includes JH1 and JH2 domains. In the SSBP2 fusion protein the N-terminal LisH domain may be analogous to the dimerization and DNA binding domains of other JAK2 fusion partners. SEC31A-JAK2 has been identified in classic Hodgkin's lymphoma while PAX5-JAK2 has been found in childhood acute lymphoblastic leukaemia.

KIF5B-ALK, PPFIBP1-ALK, SQSTM1-ALK, VCL-ALK
Novel fusion genes involving ALK have been found in a variety of cancers. In non-small cell lung cancer (NSCLC) the occurrence of KIF5B as an alternative to EML4 in ALK fusions strengthens the role of ALK signalling in the pathogenesis of NSCLC. The KIF5B-ALK fusion protein comprises the motor domain and coiled-coil domain of KIF5B and the juxtamembrane intracellular region of ALK, including the entire tyrosine kinase domain. Other novel ALK fusions include VCL-ALK which has been identified as a recurrent oncogenic mechanism in renal medullary carcinoma, a highly malignant sickle cell trait-associated cancer; PPFIBP1-ALK which has been found in pulmonary inflammatory myofibroblastic tumour; and SQSTM1-ALK which has been identified in ALK-positive large B cell lymphoma (ALK+ LBCL) where SQSTM1, a ubiquitin binding protein, replaces the more common ALK partners in ALK+ LBCL i.e. NPM1 and CLTC.

AKAP9-BRAFFusions between AKAP9 and BRAF have been identified in papillary thyroid carcinoma where it is rare in sporadic tumours and more common following radiation exposure. The fusion protein lacks the N-terminal regulatory domain of BRAF and has an intact catalytic domain. AKAP9 belongs to the group of A-kinase anchor proteins which have the common function of binding to the regulatory subunit of protein kinase A.

Systematic screen curations - Focus on pancreatic cancers:

Jones S, et al (2008). Core signalling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801-6.Analysis of over 20,000 candidate genes for DNA mutations through 114 tumours revealed high mutation rates in 12 cell signalling pathways. The curation of this publication describes the mutations from this study not included in the recent ICGC release r3, detailing 337 additional mutations.

Jiao Y, et al (2011). DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.Science 331:1199-203. This exome resequencing analysis of pancreatic neuroendocrine tumours examined the link between gene mutations and clinical prognosis, finding genes in the DAXX/ATRX, MEN1, and mTOR pathways particularly important. Full exomes were sequenced in 10 tumours, key genes followed in in a further 58; 218 mutations were described.

The following genes have been updated in this release:

ABL1, ACVR1B, AKT1, ALK, APC, ARID1A, ASXL1, ATM, BAP1, BRAF, BRCA1, BRCA2, CARD11, CBL, CDC73, CDH1, CDKN2A, CEBPA, CRLF2, CSF1R, CTNNA1,CTNNB1, CYLD, DAXX, DNMT3A, EGFR, EML4, ERBB2, ERG, EZH2, FAM123B, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, FOXL2, GATA1, GATA2, GATA3,GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, IKZF1, JAK1, JAK2, KDR, KIT, KRAS, MAP2K4, MEN1, MET, MLH1, MPL, MSH2, MSH6, NF1, NF2,NOTCH1, NOTCH2, NPM1, NRAS, PAX5, PBRM1, PDGFRA, PHOX2B, PIK3CA, PIK3R1, PPP2R1A, PRKAR1A, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1,SETD2, SMAD4, SMARCA4, SMARCB1, SMO, SOCS1, SRC, STK11, SUFU, TET2, TNFAIP3, TP53, TSHR, VHL, WT1

COSMIC v53 Total Statistics

Experiments	3432750
Tumours	604950
Samples	608042
Mutant Samples	171209
Mutations	176856
Unique Mutations	43182
Papers curated	11680
Genes	19439
Fusions	6307
Structural Variants	2752

Additional CGP resources:

The Cancer Gene Census, a listing of all genes known to be involved in cancer promotion

The Cancer Cell Line Project, defining key driver mutations in 800 common cancer cell lines

Genomics of Drug Sensitivity, Analysis of drug sensitivity data in human cancer cell lines.

CGP Copy Number Analysis in Cancer, examining tumours for gains or losses of genomic content

COSMIC v52 integrates Genomics of Drug Sensitivity

Also, 4 new genes and 16 new fusion pairs are curated from the literature, TCGA and ICGC portal data are updated and some improvements are made to COSMIC web pages.

Genomics of Drug Sensitivity in Cancer integration

The Genomics of Drug Sensitivity in Cancer, a collaborative project between the Sanger Institute and Massachusetts General Hospital, is screening a range of anti-cancer therapeutics against a large number of genetically characterized human cancer cell lines, generating drug sensitivity correlations. This release of COSMIC includes references to this work, detailing drugs where mutant gene/drug interactions have been shown to modify cell growth responses. For example, the recently described drug PLX4720 has been shown to have a significant growth modifying effect on cells containing mutant BRAF.

Cancer Gene Census update

21 new genes have been added to the cancer gene census. With the rise of large-scale genomic sequencing, the number of novel genes implicated in cancer is increasing. We aim to keep the Census up-to-date with the latest publications.

Website improvements

The front page of COSMIC has been redesigned to make it much easier to find data and sub-projects that were previously difficult to identify. For instance, the Cell Line Project, characterising the cancer genotypes of 800 common tumour cell lines has always been a significant COSMIC sub-project, and is now appropriately highlighted. Also, the FTP site which comprises export files of each release, is now much easier to find.

In addition, we have improved the informativeness of the Tissue Overview page (eg summary page for Skin). The graphic has been extended to include the top 20 genes mutated in the tissues/phenotypes selected, followed by much simpler summary of the mutation load in the selection.

Data Curation

This release (v52) of COSMIC contains full curations of 4 new cancer genes together with 16 new fusion gene pairs. In addition, our curation of TCGA data, output via the TCGA portal, has been updated with further new Ovarian serous carcinoma mutations. Also, we have completed our curation of the validated mutations in the third release of the ICGC, bringing in structural rearrangements for two Japanese Liver cancer screens, HX5T & RK-003-C

New curated genes:

DAXX and ATRX
DAXX and ATRX have been established as tumour suppressor genes in pancreatic neuroendocrine tumours. The protein product of ATRX has an ADD domain at the amino-terminus and a carboxy-terminal helicase domain, and forms a heterodimer with DAXX. The latter gene is an H3.3-specific histone chaperone.

MYD88
Highly recurrent oncogenic mutations in MYD88 have been identified in activated B-cell-like subtype of diffuse large B-cell lymphoma. MYD88 encodes an adaptor protein which mediates toll and interleukin-1 receptor signalling. The most common mutation is MYD88 L265P, which is also detected in mucosa-associated lymphoid tissue lymphoma.

CARD11
CARD11 has been identified as an oncogene in diffuse large B-cell lymphoma, particularly the activated B-cell-like subtype. The mutations commonly occur in the coiled-coil domain which mediates CARD11 oligomerization and NF-kappaB pathway activation.

New Curated Gene Fusions:

BRD4-C15orf55, BRD3-C15orf55
BRD4, from the BET family of nuclear proteins that carry 2 bromodomains and an additional extra terminal domain, functions in the regulation of cell cycle progression. It is fused to C15orf55 (NUT) in poorly differentiated (midline) carcinomas, a clinically aggressive form of carcinoma. The oncogenic fusion protein contains the N-terminal BRD4 sequence up to the serine-rich region followed by almost the entire NUT sequence. In a few cases BRD4 is replaced by the highly homologous BRD3.

PAX3-FOXO1, PAX7-FOXO1, PAX3-NCOA1, PAX3-NCOA2
FOXO1, a member of the fork head family of transcription factors, fused to either PAX3 or PAX7 is characteristic of alveolar rhabdomyosarcoma, although the former is more frequently detected. A consistent fusion protein results where the PAX DNA binding domain is fused to the fork head domain and C-terminal region of FOXO1. The novel variant translocations PAX3-NCOA1 and PAX3-NCOA2 have also been detected in rhabdomyosarcoma.

HMGA2-LPP, HMGA2-RAD51L1, HMGA2-LHFP, HMGA2-EBF1, HMGA2-CCNB1IP1, HMGA2- COX6C, HMGA2-ALDH2, HMGA2-NFIB, HMGA2-FHIT, HMGA2-WIF1
HMGA2, which encodes a protein belonging to the non-histone chromosomal high mobility group protein family, is fused to multiple partners in lipoma, pulmonary chondroid hamartoma, chondroma and uterine leiomyoma. The most common fusion is HMGA2-LPP which results in a protein consisting of the N-terminal DNA-binding domain of HMGA2 and the C-terminal LIM domain of LPP. HMGA2 fused to NFIB, FHIT and WIF1 has been detected in salivary gland pleomorphic adenomas.

The following genes have been updated in this release:

ABL1, AKT1, APC, ASXL1, ATRX, BRAF, BRCA1, BRCA2, CARD11, CBL, CDKN2A, CTNNB1, DAXX, EGFR, EML4, ERBB2, EZH2, FAM123B, FGFR3, FLT3, GATA1, GATA3, HNF1A, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MAP2K4, MEN1, MET, MPL, MYD88, NF2, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PPP2R1A, PTCH1, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, STK11, TET2, TNFAIP3, TP53, VHL

v52 Statistics

Experiments	2968661
Tumours	589549
Samples	592626
Mutant Samples	166206
Mutations	171651
Unique Mutations	42491
Papers curated	11437
Genes	19389
Fusions	6261
Structural Variants	2752

COSMIC v51 Release

Cosmic release v51 includes the curation of 3 newly identified cancer genes, 4 gene fusions and updates from the ICGC and TCGA international consortia. In addition, upgrades to the website are now available, to improve the analysis of mutation distribution within a gene, and to navigate the increasing number of curated large-scale systematic screens. Both the Genomics of Drug Sensitivity in Cancer website and the Cancer Gene Census Listing were also recently updated (in December 2010).

New genes curated from the literature:

DNMT3A
DNMT3A is a member of a family of methyltransferase enzymes which catalyse addition of methyl groups to sequences containing CpG dinucleotides. Somatic mutations have been found in 22% of adult acute myeloid leukaemia patients and are associated with poor overall survival. Over half of the case examined have a recurrent missense mutation at arginine 882. The mutations have been shown to impair normal enzymatic function and are heterozygous. These data suggest potential dominant negative activity of the mutations. Additional missense, nonsense and frame-shift mutations have also been found throughout the latter half of the gene.

BAP1
Mutational inactivation of BAP1, a tumour suppressor gene, has been identified in uveal melanomas where it coincides with metastasis. BAP1 encodes a nuclear ubiquitin carboxy-terminal hydrolase (UCH) as well as a UCH37-like domain, and binding domains for BRCA1, BARD1 and HCFC1.

GNA11
As previously described for GNAQ, mutations affecting Q209 have been found in GNA11 in melanocytic tumours. The frequency of mutations increasesprogressively from blue nevus to primary melanomas to uveal melanoma metastases; an inverse pattern to that seen with GNAQ Q209 mutations. Activation of this GTPase pathway appears to be a predominant route to the development of uveal melanoma.

New curated fusion pairs:

TAF15-NR4A3
TAF15 can replace EWSR1 as a fusion partner to NR4A3 in extraskeletal myxoid chondrosarcoma. The resulting transcript (TAF15-NR4A3) is structurally and functionally similar to the EWSR1-NR4A3 fusion.

FUS-CREB3L2, FUS-CREB3L1
FUS-CREB3L2 is tumour specific for low-grade fibromyxoid sarcoma (LGFMS) so enables the accurate diagnosis of a sarcoma with sometimes indistinct histological features. In these fusions there's a diversity of genomic breakpoints and these are often exonic rather than intronic. The rare variant FUS-CREB3L1 is occasionally detected in LGFMS.

FUS-DDIT3
Myxoid/round cell liposarcoma is characterized by the recurrent fusion FUS-DDIT3 where the 5' half of the FUS gene is fused to the entire reading frame of DDIT3, which encodes a leucine-zipper transcription factor belonging to the CCAAT/enhancer-binding protein family.

Curations of large international systematic screens:

TCGA - Full exome resequencing of Ovarian tumours
The Cancer Genome Atlas (TCGA) has recently released somatic mutation data from the exon screening of 325 serous ovarian cystadenocarcinoma tumours. We have now curated the majority of this information into COSMIC, comprising over 13,000 mutations. This can now be viewed here.

Study	Samples	Mutations
Ovarian Cystadenocarcinoma	325	13650

ICGC - Curation of third ICGC release 'Simple Mutations'
The International Cancer Genome Consortium (ICGC) has recently completed its third data release. We have curated into COSMIC all the Validated Somatic Simple Mutationdata from this ICGC release, which can be viewed in the followingstudies :

Study	Samples	Mutations
Japanese liver cancer (Riken)	1	30
Japanese liver cancer (NCC)	1	59
Breast cancer (JHU)	18	28
Colorectal cancer (JHU)	13	29
Glioblastoma Multiforme (JHU)	23	209
Pancreatic cancer (JHU)	71	1450
Glioblastoma Multiforme (TCGA)	20	29
Lung Adenocarcinoma (TSP)	21	26

Website improvements:

We have improved the Distribution section of the Histogram page, providing much more analytical pie charts. Once a gene is selected, the mutation spectrum can be explored in a number of different ways. Nucleotide substitution breakdowns are presented as pie charts, and lengths of insertions and deletions are presented as histograms. The same filters as usual can be applied to this Distribution section, including tumour phenotype, mutation type and sample source. Links are also provided to view the mutation data in tabulated detail form, and to export it for external analysis. An example of this new system, presenting the data from the KIT oncogene can be seen here.

Systematic screens:

In the last few years, cancer genome screens have been growing substantially in size, and both whole-genome and large candidate gene screens are being curated into COSMIC. As well as curating publications,we are also collecting somatic mutation information from the data portals of large international consortia, beginning with the TCGA and ICGC. A new page now makes these easier to identify and navigate, please click here.

Related CGP Resources

Genomics of Drug Sensitivity in Cancer
The Genomics of Drug Sensitivity Website was updated on 23rd December 2010 with cell line sensitivity data and genomic correlates of sensitivity for Docetaxel, Gefitinib, CI-1040, BIBW 2992 and PLX4720. This large-scale project is a joint collaboration between the Wellcome Trust Sanger Institute (WTSI) and Massachusetts General Hospital Cancer Centre to correlate genomics with response to cancer drugs in 1,000 cancer cell lines. Within the next year we plan to integrate the data from this project into the COSMIC database and develop new web-based tools to browse and mine these data. Click here to visit the site.

Cancer Cell Line Project
The Cancer Cell Line Project website holds the data from the Cancer Genome Projects large-scale systematic characterization of a panel of 770 cancer cells across 64 known cancer genes. Click here to visit the site.

Cancer Gene Census
The Cancer Gene Census was updated at the beginning of December 2010. The Census is an up-to-date listing of genes causally implicated in cancer and now stands at 436 genes. Click here to view the listing.

The following genes have been updated in this release:

ABL1, ACVR1B, AKT1, ALK, APC, ARID1A, ASXL1, ATM, BAP1, BRAF, BRCA1, BRCA2, CBL, CDC73, CDH1, CDKN2A, CEBPA, CTNNA1, CTNNB1, DNMT3A, EGFR, EML4, ERBB2, ERG, EZH2, FAM123B, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, FOXL2, GATA3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MET, MLH1, MPL, MSH2, MSH6, MYB_ENST00000341911, NF1, NF2, NOTCH2, NPM1, NRAS, PBRM1, PDGFRA, PHOX2B, PIK3CA, PPP2R1A, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SETD2, SMAD4, SMARCA4, SMARCB1, TET2, TNFAIP3, TP53, TSHR, VHL, WT1

COSMIC v51 Total Statistics

Experiments	2946792
Tumours	577304
Samples	580306
Mutant Samples	161787
Mutations	167193
Unique Mutations	41405
Papers curated	11062
Genes	19001
Fusions	5573
Structural Variants	2729

COSMIC v50 Release

Our 50th release significantly enhances the genomic focus of the COSMIC system, including a full genome browser linked directly into the COSMIC websystem. Also included are genome-wide examinations of a further 24 tumours, comprising rearrangement screens of 17 pancreatic tumours and full exome analyses of 7 renal tumours. Two new cancer genes are curated from the scientific literature, together with a further systematic screen publication.

GBrowse

With the inclusion of increasing quantities of genomic data in COSMIC, new methods to navigate and visualise this information are now required. We have implemented a version of GMOD GBrowse and linked it into COSMIC where genomic co-ordinates are available, including coding and non-coding mutations, gene footprints, structural rearrangements and copy number variants (from CONAN ). Full genome annotations have been imported from Ensembl, so that COSMIC data can be examined in the context of these full genome annotations. Throughout the COSMIC websystem, links to GBrowse are available as either links in descriptive text, or via the icon , which will present the selected data in the local genomic context.

Genome rearrangement screens of 17 Pancreatic tumours

The recent Campbell et al (2010) publication "The patterns and dynamics of genomic instability in metastatic pancreatic cancer." , describing genome structure rearrangements as early events in this cancer type, can be viewed in COSMIC, here.

Full-exome sequencing of 7 renal tumours; identification of PBRM1 gene as a tumour suppressor

The Cancer Genome Project has sequenced the full exomes of 7 renal tumours, These data, soon to be published, are available in COSMIChere.

Curation of Ding et al (2010) full-genome resequencing of 3 related breast tumours

In the Ding et al (2010) paper, 3 basal-like breast tumours were taken from one individual and their genomes were fully resequenced and comparatively analysed. We have curated the coding, non-coding and structural rearrangement mutations described in their study, available here.

New Curated genes:

ARID1A has been identified as a tumour suppressor gene in ovarian clear cell and endometrioid carcinomas. It encodes AT-rich interactive domain-containing protein 1A which is a component of the ATP-dependentchromatin modelling complex SWI/SNF.

PPP2R1A has been identified as an oncogene in ovarian clear cell carcinoma and in breast and lung carcinomas. It encodes a regulatory subunit of serine-threonine phosphatase 2 and this subunit forms the scaffold of the holoenzyme.

These curated genes have been updated this release

ABL1, AKT1, ALK, APC, ARID1A, ASXL1, ATM, BRAF, CDC73, CDH1, CEBPA, CSF1R, CTNNB1, CYLD, EGFR, EML4, ERBB2, EZH2, FBXW7, FGFR3, FLT3, FOXL2, GATA1, GNAQ, HRAS, IDH1, IDH2, JAK2, JAK3, KIT, KRAS, MEN1, MET, MLH1, MPL, NF2, NPM1, NRAS, PDGFRA, PIK3CA, PPP2R1A, PTEN, PTPN11, RUNX1, SETD2, SMARCA4, SMARCB1, STK11, TET2, TP53, TSHR, VHL, WT1

COSMIC v50 Total Statistics

Experiments	2908403
Tumours	562843
Samples	565823
Mutant Samples	142586
Mutations	147613
Unique Mutations	25601
Papers curated	10819
Genes	18660
Fusions	5112
Structural Variants	2729

COSMIC v49 Release

This release of COSMIC focuses on curation of data from the scientific literature. 57 curated genes have received updates; an additional systematic candidate gene screen has added 1121 mutations, and a further full-genome screen has contributed 45 confirmed coding mutations.

Systematic screen curations:

Shah et al (2009) describes the full-genome examination of a metastatic ER+ lobular breast cancer and compares the mutation spectrum to the primary tumour, finding 32 somatic non-synonymous coding mutations in the metastasis, but only 13 in the primary:
Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution.Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S. (2009) Nature 461:809-13.

A further analysis expanding that of Sjoblom et al (2006), Wood et al (2007) examines the same tumour set through a set of RefSeq genes additional to the earlier analysis of CCDS genes. 1121 mutations were identified, expanding the mutation spectrum defined in the earlier publication:
The genomic landscapes of human breast and colorectal cancers.Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B. (2007) Science. 318:1108-13.

These curated genes have been updated this release

ABL1, AKT1, ALK, APC, ASXL1, ATM, BRAF, BRCA1, CBL, CDKN2A, CEBPA, CRLF2, CTNNA1, CTNNB1, CYLD, EGFR, EML4, ERBB2, EZH2, FAM123B, FBXW7, FGFR2, FLT3, FOXL2, GATA1, GNAQ, GNAS, HRAS, IDH1, IDH2, JAK1, JAK2, KIT, KRAS, MEN1, MET, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PHOX2B, PIK3CA, PTCH1, PTEN, PTPN11, RB1, RUNX1, SETD2, SMARCA4, STK11, TET2, TNFAIP3, TP53, TSHR, VHL, WT1

COSMIC v49 Total Statistics

Experiments	2888511
Tumours	548399
Samples	551325
Mutant Samples	138836
Mutations	143772
Unique Mutations	25079
Papers curated	10578
Genes	18647
Fusions	5050
Structural Variants	2306

COSMIC v48 Release

This release brings the majority of curated p53 mutation data into COSMIC in collaboration with IARC, significantly improving our coverage of the key cancer genes. Other new curated genes are TET2 & SETD2, together with ten new fusion pairs. Two new systematic screens are also included. The system has been updated to provide genomic coordinates on both NCBI36 and the later GRCh37 genome builds.

TP53

In collaboration with the p53 group at IARC (http://www-p53.iarc.fr/), we have imported the majority of p53 mutation data into COSMIC. The system has been previously lacking substantial coverage of this gene, since it has been fully curated at IARC. However, our new collaboration has brought these two datasets together in COSMIC. Over 73% of the IARC Somatic dataset is now present in COSMIC, comprising a total of 20129 samples mutated, of 66242 samples analysed. The remaining of IARC's curated p53 data will become available in a later release. This p53 data can be viewed here.

Full mutation details have been curated from the scientific literature for two new genes and are now available:

SETD2, a tumour suppressor gene, encodes a histone H3 lysine 36 methyltransferase and is inactivated in clear cell renal carcinoma.

TET2, The tumour suppressor gene TET2 (ten-eleven-translocation gene, 4q 24) was found to be heterozygously deleted in MDS and Leukaemia patients whose remaining copy carried a somatic point mutation. Subsequently a wide spectrum of somatic mutations - often nonsense or frame shifts - have been found in a variety of myeloproliferative neoplasms, leukaemias (AML, sAML, CMML) and mastocytosis; These mutations are thought likely to be an early event in the pathology of these diseases and there is some evidence that TET2 is both a tumour suppressor and haematopoietic regulator.

10 new fusion gene pairs have been curated from the scientific literature:

ASPSCR1-TFE3, A characteristic translocation in alveolar soft part sarcoma results in the fusion of the N-terminal region of ASPSCR1 to the C-terminal region of TFE3. Two alternative fusion breakpoints are observed in TFE3 resulting in expression of 2 distinct fusion transcripts. ASPSCR1-TFE3 is also found in a subset of renal cell carcinomas.

PRCC-TFE3, SFPQ-TFE3, NONO-TFE3, CLTC-TFE3 Papillary renal carcinomas have fusions involving the TFE3 transcription factor gene. Most commonly the fusions are ASPSCR1-TFE3 or PRCC-TFE3 but variant translocations have also been identified in which TFE3 is fused to SFPQ, NONO or CLTC.

ETV6-NTRK3,A recurrent rearrangement in congenital (infantile) fibrosarcoma fuses the helix-loop-helix protein dimerization domain of ETV6 with the protein tyrosine kinase domain of NTRK3. ETV6-NTRK3 fusions are also found in congenital mesoblastic nephroma, a pathogenetically related tumour, and in a rare form of breast cancer, secretory carcinoma.

SLC45A3-BRAF, ESRP1-RAF1, AGTRAP-BRAF While SLC45A3-BRAF and ESRP1-RAF1 fusions have been identified in ETS rearrangement-negative prostate cancers, AGTRAP-BRAF has been found in stomach cancer; all highlighting the role of RAF pathway fusions in solid tumours.

MYB-NFIB,A recurrent fusion of the MYB oncogene to NFIB, a member of the human nuclear factor I gene family of transcription factors, has been identified in adenoid cystic carcinomas of the breast and the head and neck. The common feature of multiple splice variations is the deletion of exon 15 of MYB and its 3'-UTR.

Systematic screen curations:

Mardis et al (2009) describes the full-genome sequencing of a single AML tumour, resulting in 12 coding mutations and 52 confirmed high quality non-coding mutations, with a follow-up study examining a set of 187 AML tumours through the genes mutated in the primary sample.

Ding et al (2008) examines 188 lung adenocarcinomas through 623 genes known to be involved with cancer. 1013 mutations were described, the most mutated genes being TP53, KRAS, STK11 and EGFR.

Genome co-ordinate update to GRCh37

All genes and mutations with NCBI36 genome co-ordinates have now been updated to GRCh37. New DAS tracks have been created, and the website and data exports have been altered to include both co-ordinate systems.

These curated genes have been updated this release

ABL1, ACVR1B, AKT1, ALK, APC, ATM , BRAF, BRCA1, BRCA2, CBL, CDC73, CDH1, CDKN2A, CEBPA, CSF1R, CTNNB1, CYLD, EGFR, EML4, ERBB2, ERG, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, FOXL2, GATA1, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MEN1, MET, MLH1, MPL, MSH2, MSH6, NF1, NF2, NOTCH1, NOTCH2, NPM1, NRAS, PDGFRA, PHOX2B, PIK3CA, PRKAR1A, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SETD2, SMAD4, SMARCB1, SMO, SOCS1, SRC, STK11, SUFU, TET2, TP53, TSHR, VHL, WT1

COSMIC v48 Total Statistics

Experiments	2760220
Tumours	541928
Samples	544809
Mutant Samples	136326
Mutations	141212
Unique Mutations	23907
Papers curated	10383
Genes	18490
Fusions	4946
Structural Variants	2306

COSMIC v47 Release

This latest release of COSMIC includes six new point-mutated genes with full literature curation, together with curation of five new fusion genes involving ALK. Additionally, recent updates to the public TCGA Glioblastoma dataset have been included, as have a number of whole gene deletions interpreted from SNP6.0 microarray data. Recent publications have been curated to update sixty one other curated genes.

New curated genes

GATA2, This gene encodes a member of the GATA family of zinc-finger transcription factors and the encoded protein plays an essential role in regulating transcription of genes involved in normal haematopoietic cell differentiation and survival. Somatic mutations in GATA2 are associated with acute myeloid transformation in a subset of chronic myelogenous leukaemia (CML) patients.

GATA3, This gene encodes a protein which belongs to the GATA family of transcription factors. The protein contains two GATA-type zinc fingers; it is a regulator of T-cell development and plays an important role in endothelial cell biology. Germline mutations in this gene are found in individuals with HDR syndrome (hypoparathyroidism with sensorineural deafness and renal dysplasia). These mutations cluster in the region of the highly conserved second zinc finger. Somatic mutations in the same region have been identified in tumour tissue from both familial and sporadic breast cancer patients.

EZH2, This gene encodes a member of the Polycomb-group (PcG) family; a histone methyltransferase responsible for trimethylating Lys327 of histone H3 (H3K27). Somatic mutations have been found within the catalytic SET domain in diffuse large B-cell lymphoma and follicular lymphoma.

KDR, KDR encodes the kinase insert domain receptor, one of the two receptors of the VEGF (Vascular endothelial growth factor) - a major growth factor for endothelial cells. It is a vascular specific, type III receptor tyrosine kinase. Germline mutations of this gene are implicated in infantile capillary haemangiomas. Somatic mutations have been found in samples derived from angiosarcomas of the breast/chest wall.

CRLF2, The type I cytokine receptor subunit CRLF2 (thymic stromal lymphopoietin receptor, TSLPR) has been identified as a proto-oncogene in adult and high risk paediatric B-ALL. Over-expression is common in cases lacking rearrangements of TEL, MLL, TCF3 and BCR-ABL and can result from CRLF2 rearrangement or mutually exclusive somatic gain of function point mutations including those in CRLF2, JAK1 or JAK2. The predominant CRLF2 mutation, Phe232Cys, promotes constitutive dimerization and cytokine independent growth.

JAK1,A member of the Janus kinase family comprising JAK's 1, 2 and 3 as well as Tyk2, activating JAK1 somatic mutations have been found in the SH, pseudokinase and kinase domains of T-ALL, B-ALL and, more rarely, AML patients. Mutations have also been found in a variety of non-haematopoietic cancers. Mutations include JAK1 V658F, corresponding to the JAK2 V617F mutation commonly found in PV and ET as well as other MPNs; and R724H, corresponding to JAK2 R683 and JAK3 R657, mutations of which have been found in DS-ALL/B-ALL and DS-AMKL respectively.

New curated ALK fusion genes:

The following gene fusions have been curated from the scientific literature:
ATIC-ALK, CARS-ALK, TFG-ALK, TPM3-ALK, TPM4-ALK Variant ALK fusions, including ATIC-ALK, TPM3-ALK, TPM4-ALK and TFG-ALK, have been identified in ALK-positive anaplastic large cell lymphoma. Each translocation product retains the ALK kinase domain. ALK activation is also a recurrent oncogenic event in inflammatory myofibroblastic tumours, where this is sometimes achieved through fusion with ATIC, TPM3, TPM4 or CARS.

TCGA Glioblastoma update

We have updated our recent curation of the TCGA somatic Glioblastoma mutation data, now including phase II data direct from the public TCGA data portal. The combined data can be browsed here.

Statistics

Glioblastoma Samples	424
Genes	1,212
Sequencing Experiments	513,888
Mutations	1,243

Whole gene deletions

55 whole gene or whole-exon deletions have been defined in the core cell lines by interpretation of SNP6.0 microarray data. While many of these have been confirmed, the few unverified mutations are presented with links to the originating data for independent examination. Mutations involving the deletion of whole gene sequences have been reannotated "p.0?" in line with current HGVS recommendations.

New search system

COSMIC is now combined into the new Sanger-wide search system. This allows much richer searching, using multiple terms such as "BRAF melanoma", to much more easily find data without complex navigation through the website. The system additionally searches other Sanger genomic data, giving indications where compatible data might be found elsewhere on the Institute website.

These curated genes have been updated this release

ABL1, AKT1, ALK, APC, ASXL1, ATM, BRAF, BRCA1, BRCA2, CBL, CDH1, CDKN2A, CEBPA, CSF1R, CTNNB1, CYLD, EGFR, ERBB2, EZH2, FAM123B, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GATA1, GATA2, GATA3, HNF1A, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KDR, KIT, KRAS, MAP2K4, MEN1, MET, MLH1, MPL, MSH2, MSH6, NF1, NF2, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SMAD4, SMARCA4, SMO, SOCS1, SRC, STK11, SUFU, VHL, WT1

COSMIC v47 Total Statistics

Experiments	2564761
Tumours	464139
Samples	466851
Mutant Samples	113286
Mutations	116977
Unique Mutations	20090
Papers curated	9202
Genes	18485
Fusions	4722
Structural Variants	2306

COSMIC v46 Release

The second full-genome resequencing study from the CGP at the Sanger Institute, UK is now available, together with the curation of Parsons et al (2008), a systematic candidate gene screen of Glioblastomas. In addition, the published literature has been fully curated for fusion mutations between seven new gene pairs.

Full Genome resequencing of NCI-H209

The recent Pleasance et al (2010) publication "A small-cell lung cancer genome with complex signatures of tobacco exposure" (Nature 463, 184-190) is now available within COSMIC; please click here.

Systematic Screen Curation

The largest published candidate gene screen of Glioblastomas Parsons et al (2008), is now curated in COSMIC; please click here:

An integrated genomic analysis of human glioblastoma multiforme.Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW Science. 2008;321;1807-12. PMID: 18772396 DOI: 10.1126/science.1164382

Statistics

Samples	105
Mutations	2449

Fusion mutations between 7 new gene pairs have been curated from the literature for this release.

FUS-ERG , FUS-FEV , FUS-ATF1 Both FUS-ERG and FUS-FEV fusions have been identified as alternatives to EWSR1-ETS transcription factor fusions in Ewing's sarcoma, and FUS-ERG also occurs in t (16,21) myeloid leukaemia as well as in these solid tumours. FUS-ATF1 is found in angiomatoid fibrous histiocytoma, where the fusion of the N-terminus of FUS and the DNA binding domain of ATF1 is similar to the EWSR1-ATF1 fusion found in clear cell sarcoma.

SS18-SSX1 This fusion is characteristic for synovial sarcoma along with SS18-SSX2 and more rarely, SS18-SSX4 fusions. Through its N-terminal SNH domain SS18 protein is involved in the remodelling of chromatin structures and functions as a transcriptional activator whereas SSX proteins have 2 putative transcription-repressor domains, one of which, an SSXRD domain in the C-terminal region, is preserved in the fusion protein.

SRGAP3-RAF1 This oncogenic fusion has been identified in paediatric pilocytic astrocytoma as an alternative to the previously described KIAA1549-BRAF fusion. It also activates the ERK/MAPK pathway; the auto-inhibitory domain of RAF1 being replaced by SRGAP3.

COL1A1-PDGFB This recurrent fusion characterizes dermatofibroma protuberans and its juvenile form, giant cell fibroblastoma. The fusion consistently deletes exon 1 of PDGFB releasing this growth factor from its normal regulation. The breakpoints in COL1A1, which encodes an extracellular matrix protein, occur in various exons in the alpha-helical domain.

JAZF1-SUZ12 A fusion involving these two genes is common but not universal in endometrial stromal sarcomas, occurring less frequently in high-grade tumours. The genes encode novel proteins with zinc finger motifs and these are retained in the fusion.

The following curated genes have been updated in this release

ABL1, ACVR1B, AKT1, ALK, APC, ASXL1, ATM, BRAF, BRCA1, BRCA2, CBL, CDC73, CDH1, CDKN2A, CEBPA, CSF1R, CTNNA1, CTNNB1, CYLD, EGFR, EML4, ERBB2, ERG, FAM123B, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, FOXL2, GATA1, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KIT, KRAS, MAP2K4, MEN1, MET, MLH1, MPL, MSH2, MSH6, NF1, NF2, NOTCH1, NOTCH2, NPM1, NRAS, PDGFRA, PHOX2B, PIK3CA, PRKAR1A, PTCH1, PTEN, PTPN11, RB1, RET, RUNX1, SMAD4, SMARCA4, SMARCB1, SMO, SOCS1, SRC, STK11, SUFU, TNFAIP3, TSHR, VHL, WT1

COSMIC v46 Total Statistics

Experiments	2077858
Tumours	449676
Samples	451972
Mutant Samples	108773
Mutations	112256
Unique Mutations	19239
Papers curated	8911
Genes	18478
Fusions	4657
Structural Variants	2307

COSMIC v45 Release

The first full-genome resequencing study is now available, together with the genome-wide rearrangement screens of 24 breast tumours. In addition, five new cancer genes have been curated from the literature.

To make the data easier to investigate in depth, the website has been upgraded with new specialisation features, together with new views on mutation spectrum and distribution. Finally, we are introducing a new COSMIC Biomart, where all COSMIC's information will be available in this industry-standard data mining tool.

Full Genome resequencing of COLO-829

The recent Pleasance et al (2010) publication "A comprehensive catalogue of somatic mutations from a human cancer genome" (Nature 463, 191-196) is now available within COSMIC; please click here.

Whole-genome rearrangement screen of 24 Breast tumour samples:

Also, the CGP Stephens et al (2009) paper "Complex landscapes of somatic rearrangement in human breast cancer genomes" (Nature 462, 1005-1010) is now available in COSMIC; please click here . A paired-end genome-wide Illumina sequencing strategy revealed numerous rearrangements in very diverse patterns between the samples examined.

New genes curated from the scientific literature

GNAQ is the alpha subunit of one of the heterotrimeric GTP-binding proteins that mediate stimulation of protein kinase C signalling. Mutations in GNAQ, occurring at codon 209 in the catalytic domain, have been found as common and early mutational events in uveal melanomas.

TNFAIP3 is a negative regulator of the NF-kappa B pathway functioning through the removal of activating Lys63-linked ubiquitins and the Lys48-linked ubiquitination of receptor-interacting proteins. TNFAIP3 has been shown to be a genetic target in B-lineage lymphomas such as mucosa-associated lymphoma and Hodgkin's lymphoma of nodular sclerosing histology.

CBL encodes a protein with multiadaptor function and E3 ubiquitin ligase activity that targets a variety of tyrosine kinases for degradation. Mutations in CBL have been identified in myeloid malignancies, occurring in the critical linker and ring finger domains of the protein.

JAK3 is a member of the non-receptor tyrosine kinase family which includes JAK2. Rare but significant JAK3 activating mutations located in the JH2 (pseudokinase) and JH6 (receptor binding) domains have been found in Down syndrome and Non-DS acute megakaryoblastic leukaemia (AML-M7). Mutations have also been found in various myeloproliferative neoplasms, lymphomas and carcinomas.

NOTCH2 is a Type 1 transmembrane protein with an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. The Notch2 receptor and its 5 ligands, which include Jagged1, Jagged2, and Delta-like 1, 3 and 4, send signals that are important for development before birth. After birth,Notch2 signaling is involved in tissue repair. Mutations in the NOTCH2 gene have been identified in a small percentage of people with Alagille syndrome and malformations in the kidneys, especially in filtering structures. NOTCH2 is also preferentially expressed in mature B cells,is essential for marginal zone B-cell generation, and mutations are evident in a subset of individuals with diffuse large B-cell lymphomas.

Web site enhancements

The main histogram page of the COSMIC website had been improved to provide better ways of selecting and viewing subsets of data. In the navigation bar on the left side, new options are now available to redraw the histogram and associated tables based on four parameters: mutation type (eg deletion, nonsense substitutions, etc), sample source (cultured or tissue sample), somatic status (confirmed somatic or unknown) and systematic screen (genome-wide screen). In addition to redrawing the histogram and tables, a new "Distribution" button displays pie charts of relevant information about the data selected.

The sample summary page has also been upgraded, with every CGP sample (examined through numerous genes) receiving a mutation spectrum diagram. This comprises a histogram showing the relative frequencies of each substitution type, together with a count of insertion/deletion mutations. This is highly useful when looking for mutation signatures which may show characteristsics of, for instance, tobacco or UV light exposure.

Biomart

The new COSMIC biomart is now available, please click here. This system allows much more specialised selection of data in COSMIC and is very useful for data mining. In addition, it can be directly linked to Ensembl for federilsed querying across both databases.

The following curated genes have been updated in this release

JAK2, JAK3, MAP2K4, GNAS, MPL, SOCS1, WT1, CYLD, FBXW7, MEN1, NF1, RUNX1, ASXL1, NOTCH2, IDH1, IDH2, APC, CDH1, VHL, GNAQ, BRAF, HRAS, CEBPA, CTNNB1, FLT3, KIT, PDGFRA, PTEN, RB1, RET, SMARCB1, AKT1, EGFR, ERBB2, CDKN2A, CBL, GATA1, NPM1, PTPN11, NRAS, FGFR3, BRCA1, MSH6, PRKAR1A, KRAS, PIK3CA, MET, TNFAIP3

COSMIC v45 Total Statistics

Experiments	1654274
Tumours	434364
Samples	436577
Mutant Samples	101860
Mutations	105171
Unique Mutations	16788
Papers curated	8624
Genes	13634
Fusions	3635
Structural Variants	2249

COSMIC v44 Release

This release of COSMIC includes 4 new curated genes, 8 new curated fusion pairs and the TCGA systematic screen publication of 91 Glioblastoma tumour samples. In addition, a new CGP study is available (Adenoid cystic carcinoma) together with substantial updates to existing data.

New curated genes

IDH2 encodes a mitochondrial NADP(+)-dependent isocitrate dehydrogenase which catalyzes oxidative decarboxylation of isocitrate to alpha-ketoglutarate. It is now implicated in the pathogenesis of malignant gliomas and some secondary glioblastomas lacking IDH1 mutations have IDH2 mutations at the analogous amino acid (R172).

AKT1 encodes a serine-threonine protein kinase which is activated by phosphorylated phosphoinositides and is a central mediator of the PI3kinase signalling pathway. A common mutation (E17K) has been identified in the pleckstrin homology domain in cancers of the colon, breast, lung and ovary.

ASXL1 belongs to a family of proteins regulating chromatin remodelling. Originally implicated via aCGH on MDS/AML samples, mutations are mainly frameshift mutations, the predicted truncated proteins lack the PHD finger domain potentially compromising the function of the associated chromatin modifiers.

FOXL2, forkhead box L2 is a winged helix/forkhead transcription factor gene, encoding a nuclear protein that is specifically expressed in eyelids and in fetal and adult ovarian follicular cells. Germline mutations in FOXL2 are responsible for BPES - blepharophimosis ptosis epicanthus inversus syndrome - an autosomal dominant disorder consisting of eyelid abnormalities (only, in Type II) and ovarian failure (Type I). Somatic mutations have recently been described in ovarian granulosa cell tumours.

New curated gene fusion pairs:

The following gene fusions have been curated from the scientific literature:
EML4 / ALK
MSN / ALK
NPM1 / ALK
CLTC / ALK
SEC31A / ALK
RANBP2 / ALK
SS18 / SSX2
SS18 / SSX4

Systematic screen curation:

Comprehensive genomic characterization defines human glioblastoma genes and core pathways.The first systematic screen of the Cancer Genome Atlas Research Network (PMID 18772890) is now curated in COSMIC .

Comprehensive genomic characterization defines human glioblastoma genes and core pathways.
Cancer Genome Atlas Research Network
Nature. 2008;455;1061-8. PMID: 18772890 DOI: 10.1038/nature07385

Statistics

Glioblastoma Samples	91
Genes	599
Sequencing Experiments	54509
Mutations	662

New CGP resequencing study: Adenoid Cystic Carcinoma Candidate Gene Screen

Adenoid cystic carcinoma is a slow growing tumour of the secretory glands, arising most commonly in the salivary glands but also occurring in other parts of the body. As part of an ongoing research effort funded by the Adenoid Cystic Carcinoma Research Fund (www.accrf.org), 400 candidate gene (including genes implicated in cancer, cell signaling and growth control) were sequenced for small point mutations. This work was carried out on 25 samples (provided by ACCRF collaborative research group member Dr. Adel El-Naggar) utilising an approach of PCR product generation for the entire set of PCR amplimers followed by individual concatentation of all amplimers for each tumour and matching normal DNA sample, then sequencing this material utilising next generation sequencing. In total 8 somatic point mutations were identified in 8 genes. No highly prevalent point mutation was identified in this set of genes.

These curated genes have been updated this release

KRAS, PIK3CA, FGFR2, MET, ABL1, FGFR1, JAK2, MAP2K4, GNAS, EML4, FOXL2, PTCH1, MPL, SOCS1, HNF1A, WT1, NF2, CYLD, FBXW7, MEN1, NF1, RUNX1, IDH1, IDH2, ASXL1, FAM123B, APC, CDH1, SMAD4, VHL, BRAF, HRAS, CEBPA, CSF1R, CTNNB1, FLT3, KIT, PDGFRA, PTEN, RB1, RET, SMARCB1, SUFU, ACVR1B, AKT1, ALK, ATM, EGFR, ERBB2, SRC, STK11, CDKN2A, GATA1, SMO, NOTCH1, NPM1, PTPN11, NRAS, FGFR3, BRCA1, BRCA2, MLH1, MSH2, MSH6, PRKAR1A

COSMIC v44 Total Statistics

Experiments	1631186
Tumours	419018
Samples	421193
Mutant Samples	97932
Mutations	101138
Unique Mutations	16072
Papers curated	8336
Genes	13501
Fusions	3521
Structural Variants	40

COSMIC v43 Release

The COSMIC curation systems have been extended to encompass the entry of large-scale systematic screen papers. For this release, we have entered the first such paper, the Sjoblom et al (2006) screen of human breast and colorectal cancers. This release also contains two new genes successfully curated from the scientific literature (IDH1, SMARCA4) and the finalisation of two of the Cancer Genome Project's current resequencing studies.

Systematic Screen Papers Curated in COSMIC

For this release of COSMIC we have entered the Sjoblom et al (2006) systematic screen paper of human breast and colorectal cancers. An additional 8,648 genes have been added to COSMIC along with the 1,672 mutations from the paper. The COSMIC reference overview page for this publication is available here.

The consensus coding sequences of human breast and colorectal cancers. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. Science. 2006 Oct 13;314(5797):268-74. Epub 2006 Sep 7. PMID: 16959974

CGP resequencing studies completed

The resequencing of candidate genes in Pilot and Renal tumour sets has now been completed. The finalised studies examined 2978 samples through 4766 genes, discovering a total of 5437 mutations. All of these can be found in COSMIC's CGP Resequencing Studies Site.

New curated genes

IDH1 is a catalytic enzyme causing NADP+ dependent oxidative decarboxylation of isocitric acid. It plays an important role in the control of glucose-stimulated insulin secretion and the cholesterol and fatty acid biosynthetic pathways. Originally implicated in human cancer in genome-wide sequencing scans, when mutated it is an indicator for the longer survival of these patients.

SMARCA4, is a scaffold protein, forming a functional part of the SWI/SNF complex involved in the control of transcription.

These curated genes have been updated this release

FBXW7, MEN1, NF1, BRAF, HRAS, CSF1R, CTNNB1, FLT3, KIT, PDGFRA, PTEN, RET, SMARCB1, SUFU, ACVR1B, ATM, EGFR, ERBB2, SRC, CDKN2A, FAM123B, GATA1, SMO, NOTCH1, NPM1, PTPN11, NRAS, FGFR3, BRCA1, BRCA2, APC, CDH1, SMAD4, VHL, TSHR, MLH1, MSH2, MSH6, SMARCA4, RUNX1, PHOX2B, GNAS, KRAS, PIK3CA, FGFR2, FGFR1, IDH1, JAK2, JAK3, MAP2K4, TET2, PRKAR1A, CDC73, PTCH1, MPL, CTNNA1, SOCS1, HNF1A, WT1, ERG, NF2

COSMIC v43 Total Statistics

Experiments	1506545
Tumours	366477
Samples	368592
Mutant Samples	85749
Mutations	88727
Unique Mutations	14971
Papers curated	7797
Genes	13423
Fusions	2770
Structural Variants	40

COSMIC v42 Release

For this release of COSMIC two known cancer genes (GNAS and ALK) and 3gene fusions (FCHSD1 / BRAF, KIAA1549 / BRAF, EWSR1 / NR4A3) have beensuccessfully curated from the scientific literature. The Cancer CellLine Project has also been updated with the addition of 80 mutations.

Cancer Cell Line Project Update

The Cancer Cell Line Data has been updated with the addition of 80 mutations. The project has also published a further set of variants identified by the screen which have been classified as Tentatively Oncogenic Variant (TOV) or Unknown Variant (UV). These variants are currently available from our website as an excel file.

Curation of known cancer genes ALK and GNAS

Two further cancer genes have been curated with the addition of 95mutations for ALK and 235 mutations for GNAS.

Curation of gene fusions

The following gene fusions have been curated from the scientificliterature:
FCHSD1 / BRAF
KIAA1549 / BRAF
EWSR1 / NR4A3

Genes updated:KRAS, PIK3CA, ABL1, FGFR1, JAK2, BRAF, HRAS, CEBPA, CSF1R, CTNNB1, KIT, PDGFRA, PTEN, RB1, SUFU, ERBB2, SRC, STK11, CDKN2A, GATA1, SMO, NPM1, PTPN11, NRAS, BRCA2, MLH1, MSH2, MSH6, APC, CDH1, SMAD4, MET, EGFR, FLT3, PTCH1, MPL, WT1, CYLD, FBXW7, NF1, ALK, FGFR3, RET, NOTCH1, NF2, GNAS

COSMIC v42 Total Statistics

Experiments	1111579
Tumours	339481
Samples	341522
Mutant Samples	76132
Mutations	78933
Unique Mutations	12905
Papers curated	7386
Genes	4775
Fusions	2424
Structural Variants	40

COSMIC v41 release

This release of COSMIC comprises an update of published data in which 44 genes have been updated with the addition of 22516 samples and a further 7387 mutations.

Gene Update

STK11, CDKN2A, GATA1, SMO, NPM1, PTPN11, NRAS, BRCA2, MSH2, KRAS, PIK3CA, JAK2, MAP2K4, BRAF, HRAS, CEBPA, CTNNB1, KIT, PDGFRA, PTEN, RB1, ATM, ERBB2, FBXW7, NF1, FAM123B, APC, CDH1, VHL, MET, EGFR, FLT3, PTCH1, MPL, SOCS1, HNF1A, WT1, CYLD, FGFR3, RET, RUNX1, TSHR, PHOX2B, NOTCH1.

COSMIC v41 Total Statistics

Experiments	1078748
Tumours	313780
Samples	315778
Mutant Samples	70086
Mutations	72718
Unique Mutations	12349
Papers curated	6876
Genes	4773
Fusions	2266
Structural Variants	40

COSMIC release 40

This release of COSMIC comprises an update of the existing genes totalling almost 3000 new mutations.

Gene Update

2947 new mutations have been added in release 40; the following curated genes have been updated:BRAF, HRAS, CEBPA, CTNNB1, KIT, PDGFRA, PTEN, ERBB2, MLH1, MSH2, KRAS, PIK3CA, JAK2, CDKN2A, GATA1, NPM1, PTPN11, NRAS, FAM123B, APC, VHL, MET, EGFR, FLT3, PTCH1, MPL, HNF1A, FBXW7, PRKAR1A, RUNX1, FGFR3, RET, TSHR, NOTCH1

Cancer Gene Census

On the 5th November, the Cancer Gene Census was brought up to date, with the addition of three genes newly identified in the causation of cancer, IDH1, MDM2, KIAA1549.

COSMIC v40 Total Statistics

Experiments	1050480
Tumours	291551
Samples	293262
Mutant Samples	62930
Mutations	65331
Unique Mutations	11789
Papers curated	6486
Genes	4773
Fusions	2266
Structural Variants	40

COSMIC release 39, Annotating Cancer Genomes

For this release of COSMIC the database and web interfaces have been upgraded to handle Next Generation Sequencing Data. This is part of ongoing work to allow COSMIC to handle the increased volumes and complexity of somatic data that is anticipated from Next Generation Sequencers. In particular, for this release we have concentrated on adapting COSMIC to handle large-scale structural variants (including translocations, large insertions/deletions, inversions, and duplications).

The structural variants from the Campbell et al. 2008 paper, which comprehensively characterizes 2 lung cancer cell lines, have been entered into COSMIC (click here for study overview). Sample Summary pages are available for both cancer cell lines (NCI-H2171 and NCI-H1770).

Circular plots (Circos plots developed by Martin Krzywinski) have been added to the sample overview page which gives a clear overview of all the structural variants along with copy number changes and COSMIC point mutations for a particular sample (Figure 1). More detailed views of complex rearrangements are available on the mutation details page.

Figure 1. Circos Plot showing structural variants in relation to copy number and COSMIC Point Mutations.

Tabular views and exports are also available for these data (Figure 2). Due to the complexity of these rearrangements, where possible, a short description term of the variant is given (e.g. deletion, tandem duplication translocation). The variant is also fully described using HGVS mutation nomenclature. For example chr11:g.36585230_76606619del, where chr11: denotes the chromosome involved, g. for genomic coordinates, 36585230 for the deletion start point, 76606619 for deletion end point and del indicates a deletion event.

Figure 2. Summary Structural Variants Table

Bioinformatics Primer on COSMIC published

NCI/Nature Pathway Interaction Database Primer on COSMIC published and is available from here.

Update of the Cancer Gene Census

The Cancer Gene Census was updated on 11th August 2008. The Census now contains information of 379 genes of which 343 harbour somatic alterations and 70 germline.

COSMIC v39 General Statistics

Experiments	1035943
Tumours	281307
Samples	282777
Mutant Samples	60007
Mutations	62352
Unique Mutations	11642
Papers curated	6168
Genes	4773
Fusions	2266
Structural Variants	40

COSMIC release 38

For this release of COSMIC we have concentrated our efforts on significantly updating the following genes:BRAF, HRAS, CTNNB1, KIT, PDGFRA, PTEN, RB1, ERBB2, MAP2K4, CDKN2A, GATA1, SMO, NPM1, NRAS, MLH1, MSH2, KRAS, PIK3CA, JAK2, APC, SMAD4, EGFR, FLT3, PTCH1, MPL, HNF1A, FBXW7, NF1, FGFR3, RET, NF2, NOTCH1.

External links

In collaboration with the Human Gene Nomenclature committee (HGNC) and the Atlas of Genetics and Cytogenetics in Oncology and Haematology (Atlas Genetics Oncology), links are now available from COSMIC's gene summary page to further information at these resources.

A Current Protocol for COSMIC

An article describing COSMIC, its contents and usage, has been published in Current Protocols in Human Genetics, unit 10.11. Describing in detail how the website and exported datasheets may be used and interpreted, this is available at the Wiley Interscience website.

COSMIC v38 total statistics

Experiments	1019304
Tumours	268938
Samples	270095
Mutant Samples	56918
Mutations	59187
Unique Mutations	11400
Papers curated	5902
Genes	4773
Fusions	2266

COSMIC release 37

This months release extends our complete curation of oncogenic EWSR1 fusion partners, together with two new curated genes, PHOX2B & PRKAR1A. CGP's resequencing studies and cell line projects are also significantly updated, each receiving over 100 new mutations. In total, over 1200 new mutations have been added to COSMIC this release.

Curated genes

PHOX2BThis gene encodes a highly conserved homeobox transcription factor known to cause congenital central hypoventilation syndrome with associated neuroblastoma.

PRKAR1AThis is a regulatory subunit of the cAMP dependent protein kinase holoenzyme. An apparent tumour suppressor gene, it has also been observed to be oncogenic in fusions with RET and RARA.

Gene	Unique Samples	Samples	Experiments	Mutants	Papers	Mutations	Unique Mutations
PHOX2B	410	410	411	6	4	6	5
PRKAR1A	232	232	233	7	5	7	7

Curated EWSR1 fusions

EWSR1/ETV4; EWSR1/FEV; EWSR1/PATZ1; EWSR1/PBX1; EWSR1/POU5F1; EWSR1/ZNF384

EWSR1 has been observed in oncogenic gene fusions with over 15 partners. This month we release our curation of the literature describing its fusion with a further six partners, bringing the total to 14.

Genes	Unique Breakpoints	Mutations	Unique Fusions	Papers	Mutant Samples
EWSR1 / ETV4	3	6	4	2	3
EWSR1 / FEV	5	10	4	4	5
EWSR1 / PATZ1	1	2	2	1	1
EWSR1 / PBX1	1	3	3	1	1
EWSR1 / POU5F1	5	10	4	2	5
EWSR1 / ZNF384	2	4	4	1	2

The following curated genes have received significant updates:BRAF, HRAS, KIT, PTEN, RB1, SMARCB1, ERBB2, STK11, CDKN2A, PTPN11, NRAS, BRCA2, MLH1, MSH2, KRAS, PIK3CA, JAK2, APC, VHL, MSH6, MET, EGFR, MPL, FBXW7, PRKAR1A, RET, RUNX1, NOTCH1, NF2, PHOX2B.

COSMIC v37 total statistics

Experiments	1006553
Tumours	258584
Samples	259684
Mutant Samples	53569
Mutations	55779
Unique Mutations	11207
Papers curated	5706
Genes	4773
Fusions	2249

COSMIC release 36

The March 2008 release of COSMIC contains full curation of the TSHR gene together with a further 6 EWSR1 gene fusion pairs.

Curated genes

TSHR - Thyroid stimulating hormone receptor is a 7-TM cell surface receptor expressed in follicular thyroid cells. Upon binding of its ligand, thyrotropin, a signalling cascade is commenced resulting in a range of transcriptional alterations. Somatic mutations in this gene have been described in thyroid adenomas and carcinomas.

Gene	Samples	Experiments	Mutants	Papers	Mutations	Unique Mutations
TSHR	665	669	210	36	210	61

Curated Fusions

EWSR1/ATF1 ; EWSR1/CREB1 ;EWSR1/DDIT3 ; EWSR1/ETV1 ; EWSR1/SP3 ;EWSR1/WT1
EWSR1 is fused to multiple partner genes via recurrent chromosomaltranslocation in, primarily, Ewing sarcoma. We are currently curating the complete mutation data for this gene, which has so far been fused with over 10 partners; we have released our curation of EWSR1 with ERG & FLI1, we now release the data for six more gene partners.

Genes	Mutant Samples	Mutations	Unique fusions	Papers
EWSR1 / ATF1	72	175	16	17
EWSR1 / CREB1	24	36	5	3
EWSR1 / DDIT3	11	22	7	6
EWSR1 / ETV1	4	7	3	3
EWSR1 / SP3	1	3	3	1
EWSR1 / WT1	102	198	22	28

The following curated genes have received significant updates:
BRAF, BRCA1, BRCA2, CDH1, CDKN2A, CEBPA, EGFR, ERBB2, FLT3, HRAS, KRAS, MLH1, MSH2, MSH6, NF2, NRAS, PDGFRA, PTEN, SMARCB1, STK11, TSHR, VHL

COSMIC v36 total statistics

Experiments	1000842
Tumours	254673
Samples	255767
Mutant Samples	52343
Mutations	54519
Unique Mutations	10995
Papers curated	5614
Genes	4772
Fusions	2174

COSMIC release 35

This release of COSMIC contains the new curation of four new tumour suppressor genes, and further curation of EWSR1/FLI1 gene fusions in Ewing's sarcoma. We also announce a significant upgrade to the CGP Trace Archive, which is now updated daily with our latest sequencing results.

Literature Curation

MLH1

MLH1 is a tumour suppressor gene, involved in mismatch repair. The encoded protein is a subunit of the large 'BRCA1-associated genome surveillance complex' (BASC) involved in DNA damage detection and repair. This particular subunit dimerises with PMS2 to provide endonuclease capacity within the complex. MLH1 germline mutations give rise to HNPCC (hereditary non-polyposis colorectal cancer). Somatic mutations in this gene are important in sporadic colorectal cancers. Mutations of MLH1 lead to a mutator phenotype often manifested by microsatellite instability.

MSH2

MSH2 is a tumour suppressor gene, also involved in mismatch repair. It resides within the 'BRCA1-associated genome surveillance complex' (BASC) which detects and repairs DNA damage. MSH2, in complex with MSH6, forms a sliding clamp which traverses the DNA backbone detecting mismatched bases. MSH2 germline mutations also give rise to HNPCC. Similar to MLH1, somatic mutations in MSH2 are found predominantly in colorectal cancers. Mutations of MSH2 lead to a mutator phenotype often manifested by microsatellite instability.

CDC73

CDC73 (HRPT2) is a tumour suppressor forming part of the PAF protein complex, which is associated with RNA polymerase II and may therefore be involved in both initiation of RNA synthesis and RNA elongation. Mutations in this gene have been identified in tumours of the parathyroid, most often causing the endocrine disorder hyperparathyroidism (with or without jaw tumour).

MAP2K4

MAP2K4 is one part of the mitogen-activated protein kinase (MAPK) pathway, a signal transduction cascade which mediates certain extracellular signals via RAS/RAF resulting in transcriptional control of a wide range of genes. The MAP2K family of peptides regulate MAPK activity by phosphorylation. MAP2K4 mutations appear involved in many tumour types.

Gene	Samples	Experiments	Mutations	Unique Mutations	Papers
MLH1	1328	1325	44	38	25
MSH2	1306	1304	36	33	23
CDC73	278	272	39	32	11
MAP2K4	1557	1559	22	19	9

EWSR1/FLI1 Gene fusions

Ewing's sarcoma is a rare bone tumour, infrequently of extraskeletal origin, most frequently occurring in teenage children. The majority of these tumours contain a t(11;22)(q24;q12) translocation which fuses the EWSR1 gene on chromosome 22 with the FLI1 gene on chromosome 11. We have now curated the existing literature describing fusions between this gene pair.

Genes	Mutant Samples	Papers	Unique Mutations
EWSR1/FLI1	1133	115	28

The following curated genes have been updated for this release:CDKN2A, PTPN11, NRAS, MLH1, MSH2, KRAS, JAK2, MAP2K4, BRAF, HRAS, CTNNB1, MEN1, NF1, APC, VHL, EGFR, FLT3, PTCH, MPL, WT1, RET, CDC73, RUNX1, EWSR1, FLI1.

Web site upgrade

Genomic co-ordinates for individual mutations are now available in the data export section, together with the datasheets in the FTP site.

CGP Trace Archive

The CGP trace archive has been updated to contain all the sequencing traces used in our analysis of the samples and genes presented in the CGP Resequencing project (COSMIC red pages). The number of traces available for download is now approaching 9.5 million. The Archive itself has also been upgraded, so that it receives daily updates of CGP sequencing traces as they pass through our sequencing pipeline. Daily updates are available as separate files; these will be integrated into the main download files once per week.

Samples with trace data	Total number of traces available
276	9465645

COSMIC Statistics

Experiments	991743
Tumours	250869
Samples	251847
Mutant Samples	50949
Mutations	53098
Unique Mutations	10779
Papers curated	5449
Genes	4763
Fusions	1957

COSMIC 34

This release of COSMIC includes the addition of BRCA1, BRCA2, and EWSR1/ERG gene fusion from the scientific literature. The website has been enhanced with an update of old gene names and the addition of further links (NCBI Entrez Gene, CCDS, Swiss-Prot and TrEMBL). The CGP Trace and Genotype Archive holding the groups sequence traces and genotype data is also now available.

Literature Curation

BRCA1 and BRCA2

BRCA1 and BRCA2 are tumour suppressor genes initially identified as inherited cancer susceptibility genes for breast and ovarian cancer. Both proteins been shown to have roles in genome surveillance, detection of DNA damage and its subsequent repair. However, they associate with different DNA repair complexes and generate different tumour histologies and spectra. Somatic mutations of either gene are rare, with BRCA2 being more frequently found to have somatic mutations, particularly in ovarian and pancreatic carcinomas.

We report that mutations in these two genes have been discovered at fairly low frequencies (2-3%), with BRCA2 mutated in a wider tissue range than BRCA1.

Gene	Unique Samples	Samples	Experiments	Mutant Samples	Papers	Mutations	Unique Mutations
BRCA1	1106	1106	1114	25	22	25	23
BRCA2	1142	1146	1145	29	16	33	29

EWSR1/ERG fusion

Fusions of EWSR1 and ERG are common events in skeletal (and the rarer extraskeletal) Ewing's Sarcoma. These fusions, found at a frequency of approximately 10% in bone tumours result from complex rearrangements, since the two partner genes are not transcribed in the same chromosomal direction.

Genes	Mutant Samples	Papers	Unique Mutations
EWSR1/ERG	77	49	11

COSMIC Data Updates

The CGP Resequencing screens and the following curated genes havereceived updates: BRAF, HRAS, CSF1R, CTNNB1, KIT, PDGFRA, PTEN, ACVR1B, ATM, ERBB2, BRCA1, BRCA2, KRAS, PIK3CA, FGFR2, ABL1, FGFR1, JAK2, SRC, STK11, CDKN2A, PTPN11, NRAS, FAM123B, APC, SMAD4, VHL, MSH6, MET, EGFR, FLT3, FBXW7, MEN1, NF1, RUNX1, FGFR3, RET.

CGP Trace and Genotype Archive

The groups sequence traces and genotype data are now available from the CGP Trace and Genotype Archive site. In order to access the data a Data Transfer Agreement must be completed and approved. A unique username and password will then be provided to access this resource.

Samples with trace data	276
Samples with genotyping data	1,135
Total number of traces	7,254,445

Gene Name Update

244 genes had their names updated (5.2%). It is still possible to search by the old gene name.

Website Upgrades

There has been an addition of several external gene links on the gene summary page. This includes links to NCBI Entrez gene, CCDS, Swiss-Prot and TrEMBL.

The sample summary page now also contains sample source information.

General Statistics

Experiments	984673
Tumours	246369
Mutant Samples	50032
Mutations	52146
Unique Mutations	10533
Papers curated	5271
Genes	4762
Fusions	685

COSMIC 33: Improved CGP data release

The WTSI Cancer Genome Project (CGP) announces an updated data release policy. We will now be releasing confirmed somatic mutations on a bi-monthly basis. Confirmed and annotated somatic mutations identified in the previous two months will be released in COSMIC, continuing on at two-monthly intervals. Data will still appear within current COSMIC architecture of gene family/gene set and under appropriate studies. This new policy will result in expedited pre-publication release of curated somatic mutations as they are identified.

This new data will be available in the COSMIC blue pages, but will be most noticeable in COSMIC's CGP resequencing studies site (red pages), as this distinguishes CGP data from the literature curation.

CGP resequencing data is broadly divided (in the red pages) into 3 categories, 'Kinase', 'Pilot' and a new project, 'Renal'. Whilst the Kinase data is completed and published, the other two studies are much larger and still in progress. A collection of approximately 4000 genes has been selected for resequencing in a set of 40 matched pair cell lines ('Pilot' project) and 96 primary clear cell renal cancers. Each tumour sample in these projects has a matched normal sample, whichallows the distinction of somatic mutations from germline variants. The pilot project currently comprises 1865 somatic sequence changes, whilst the Renal project, although less advanced than the Pilot, has identified 84 mutations to date. These will be automatically updated with all our confirmed data every bimonthly release.

Literature curation

RUNX1 (AML1) has been fully curated

RUNX1 is one subunit of the PEBP2 transcription factor, binding to DNA at enhancer sequences. This gene is one of the most frequent targets of chromosome translocations associated with leukemia. Small somatic mutations have also been observed, most frequently in myeloblastic leukaemia types (Acute myeloblastic Leukaemia, MyeloDysplastic Syndrome) and it is these that we have curated in COSMIC. Our data suggests a somatic mutation rate of approximately 10% in this phenotype.

Curated Gene Update

The following curated genes have received updates from the literature:APC, ATM, BRAF, CDH1, CDKN2A, CTNNA1, CTNNB1, CYLD, EGFR, ERBB2, ERG, ETV1, FBXW7, FGFR3, FLT3, GATA1, HRAS, JAK2, KIT, KRAS, MADH4, MPL, MSH6, NF1, NF2, NOTCH1, NPM1, NRAS, PIK3CA, PTCH, PTEN, PTPN11, RB1, RET, SMARCB1, SMO, SOCS1, STK11, SUFU, TMPRSS2, VHL, WT1, WTX.

General Statistics

This release includes 1563 new mutations identified in the set of 4799 genes; 1495 genes are new this month.

Experiments	968416
Tumours	239766
Mutant Samples	48959
Mutations	51054
Unique Mutations	10390
Papers curated	5103
Genes	4799
Fusions	445

COSMIC v32

This release includes four new tumour suppressor genes and improved availability in Ensembl.

New external integration: Ensembl

We are continually striving to improve the utility of the data in COSMIC by integrating it closely with external resources. In this release, we provide a much closer integration with the Ensembl genome browser than previously. All our gene & mutation data now have location coordinates on the NCBI36 genome sequence, allowing us to use Ensembl "DAS" technology to display this information within their genome browser, aligned with their standard genome annotations. We have made this easily available, via a single link from our pages.

Literature curation

Four new tumour suppressor genes have been introduced to COSMIC this month, all receiving full literature curation of their somatic mutation data.

NF1

Neurofibromatosis is a familial disease with a complex phenotype including tumours of the central nervous system, caused by mutations in the NF1 tumour suppressor gene. Somatic mutations in tumours have also been identified in this gene, and it is these that we have fully curated.

NF2

The central form of neurofibromatosis is a similar familial central nervous system tumour syndrome, caused by mutations in the NF2 tumour suppressor gene. Somatic mutations in tumours have also been identified in this gene, and it is these that we have fully curated.

SOCS1

SOCS1 downregulates cellular cytokine signalling by its direct interaction with JAK1. It was first implicated in cancer after aberrant methylation was observed to inactivate its activity causing Hepatocellular Carcinoma. Somatic mutations have also been observed which inactivate this tumour suppressor and these have been curated.

TCF1

TCF1 binds to the promoters of several (largely liver-specific) genes, to enhance their expression. Somatic and germline mutations in this gene have been found which cause liver adenomas, and we have curated the somatic component.

The following curated genes have received updates from the scientific literature: KRAS, PIK3CA, JAK2, BRAF, HRAS, KIT, PDGFRA, PTEN, CDKN2A, VHL, EGFR, FBXW7, MEN1, RET

General Statistics for this release

Experiments	521624
Tumours	235207
Mutant Samples	47470
Mutations	49491
Unique Mutations	9699
Papers curated	5053
Genes	3304
Fusions	445

COSMIC (v31) now includes Gene Fusion Data

The CGP COSMIC team is pleased to announce the addition of gene fusion/translocation somatic mutation data from the literature to thedatabase. Currently, the census of known cancer genes is dominated by somatically generated fusion genes that have been identified primarily in leukaemias, lymphomas and soft tissue tumours. Until now, we have concentrated on curating somatically point mutated cancer genes for COSMIC. Almost all known cancer genes that have somatic point mutations are, however, now curated in COSMIC. In the coming months we will therefore be searching the scientific literature and annotating genes involved in gene fusions and their partners for addition into the COSMIC database.

We have launched this new facility, complete with new views for this data type, with the curation of TMPRSS2, a gene frequently found to be fused to ETS family transcription factors in adenocarcinoma of the prostate. These mutations have served to spur increased investigation into the potential role of fusion genes in adult solid tumours. The move to curate fusion genes is an important addition and will further enhance COSMIC as the most comprehensive source for somatic mutation data from human cancers.

Fusion Gene Pairs

TMPRSS2/ETV1

TMPRSS2/ERG

Website Upgrades

The fusion data has been integrated into existing pages and overviewed in new pages: Translocations Overview and Translocations Summary.

This new data can be viewed graphically and textually.

The image above shows the table of inferred breakpoints (determined from a sample's observed fusion mRNA spectrum) for a fusion gene pair.

The image above shows a graphical representation of the observed mRNA transcripts from which the inferred breakpoints are calculated.

Further information of the new gene fusion website features is available in the help pages.

Genes from Literature Curation

A new homepage has been created for genes which have received full curation of the scientific literature. This is a new page which allows the distinction of these genes from CGP's data release, for which no literature has been curated.

Curated Gene Update

The following curated genes have also received updates from the scientific literature: CDKN2A, GATA1, NOTCH1, NPM1, NRAS, JAK2, KRAS, PIK3CA, BRAF, HRAS, CEBPA, CSF1R, CTNNB1, KIT, PDGFRA, PTEN, RB1, MET, EGFR, FLT3, WT1, APC, MADH4, FBXW7, FGFR3.

General Statistics for this release

Experiments	515535
Tumours	230057
Mutant Samples	46978
Mutations	48911
Unique Mutations	9014
Papers curated	4938
Genes	3302
Fusions	438

COSMIC v30

Today we release full literature curations of five tumour suppressor genes MEN1, ATM, CYLD, FBXW7, WTX; 4712 samples were examined in 112 papers, recording 468 mutations. Additionally, we release two new CGP resequencing studies which add a further 91 new genes to COSMIC.

Literature Curation

Curation of the scientific literature has been completed for five new genes from the cancer census. All five genes are tumour suppressors, causing phenotypes via their inactivation:

MEN1 (Multiple Endocrine Neoplasia Type 1)

Somatic mutations in this gene have been found in tumours from several endocrine sites, recapitulating those seen in patients carrying germline mutations including tumours in the pituitary, pancreas and parathyroid. MEN1 encodes a nuclear protein thought to be a transcriptional regulator.

CYLD (Cylindromatosis)

This gene has been found to have mutations in sporadic cylindromas, tumours arising from skin adnexal structures (such as hair follicles and glands), principally on the face and scalp. CYLD encodes a deubiquitinating enzyme regulating cell signalling including the NF-kappaB pathway.

FBXW7 (CDC4)

Mutations inactivating FBXW7 have been found in a range of cancer types including colorectal, ovarian and T-ALL. The protein is involved targeting a number of key proteins, including NOTCH1 and MYC, for ubiquitin-mediated degradation.

ATM

This gene encodes a protein kinase involved in cell cycle checkpoint control. Amongst other key cell cycle components, it has been shown to phosphorylate TP53 and CHEK2 in response to DNA damage. Germline mutations causes Ataxia-telangiectasia (AT) a recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy, primarily lymphoid in origin.

WTX (FAM123B)

Recently discovered, WTX is inactivated in approximately 30% of Wilms Tumours. Located on the X chromosome, this tumour suppressor only requires a 'single-hit' for tumourigenic inactivation.

New tumour suppressor gene statistics:

Gene	Samples	Experiments	Mutations	Papers
MEN1	1680	1683	196	66
ATM	1714	1692	198	33
FBXW7	1207	1204	60	10
WTX	82	82	7	1
CYLD	29	29	7	2

The following curated genes have also received updates: BRAF,HRAS,CEBPA,CTNNB1,KIT,PDGFRA,PTEN,SMARCB1,ERBB2,JAK2,CDKN2A,PTPN11,NRAS,KRAS,PIK3CA,APC,CDH1,MADH4,EGFR,FLT3,MPL,WT1,FGFR3

CGP resequencing studies

91 new genes have been examined in our pilot set of matched pair cell lines, resulting in the discovery of 22 new mutations:

Study	Genes	Experiments	Samples	Mutations
Integrin alpha family	16	640	40	11
Miscellaneous genes of interest from literature sources	75	3000	40	11

General Statistics for this release

Experiments	499958
Tumours	217944
Mutant Samples	44491
Mutations	46364
Unique Mutations	8855
Papers curated	4794
Genes	3302

COSMIC v29 released

COSMIC release 29 includes 22 new CGP resequencing studies, comprising 567 new genes within which 192 new mutations have been identified. Additional updates to our curation of the scientific literature have also been included, adding a total of 1041 mutations to this release.

CGP Resequencing Studies

567 genes have been examined in our pilot set of matched pair cell lines:



2

Study	Genes	Mutations
PAX transcription factor family	11	5
Tripartite motif-containing protein family	56	28
Genes on APC/CTNNB1 pathway	59	25
FK506/rapamycin binding protein family	26	5
Diacylglycerol kinases and other lipid kinases	18	17
SMAD protein family	24	7
Histone acetyltransferase	7	2
Dual specificity phosphatases	23	2
Genes associated with ERB family of RTKs	8	3
Genes associated with MYC proteins	21	12
Ubiquitin specific peptidase family	50	16
C-X-C/C-C motif chemokine receptor genes	19	8
Essential For Cell Division - derived from a siRNA screen in human cells	21	5
Genes from RNAi TSG gene screen	5
Glycolysis associated genes	23	4
Integrin beta family	8	8
Small ubiquitin-like modifier (SUMO) protein family	14	2
14_3_3 family of scaffold protein	8	1
STAT and SOCS gene families	43	7
Serpin/TIMP peptidase inhibitor families	46	17
Sorting NeXin family	27	3
Genes associated with RAS proteins	53	13

Literature curation

89 new publications have been curated, updating the information for the following genes: JAK2,HRAS,CEBPA,PTEN,RB1,RET,ERBB2,CDKN2A,GATA1,NRAS,KRAS,PIK3CA,EGFR,CTNNA1,APC,CDH1,MADH4

General Statistics for this release

Experiments	482902
Tumours	206972
Mutant Samples	42266
Mutations	44062
Unique Mutations	8420
Papers curated	4515
Genes	3220

COSMIC v28 Released

This months COSMIC release comprises a substantial increase in the CGP resequencing data, adding 1033 new genes to the system, together with updates to the scientific literature curation.

CGP Resequencing Studies

26 new studies have been included in this release, containing 1033 new genes which have been examined through the pilot matched pair cell line set.

Study	Genes	Mutations
ADAM metallopeptidase family	40	27
Cyclins and Genes associated with RB	68	20
Nfkappa signalling family	58	14
Phospholipase C Family	13	16
Protein Kinase anchor proteins	32	15
Ral Guanine nucleotide dissociation factors	6	3
Hypoxia inducible factor pathway	23	11
SerThr Phosphotases (PPP)	69	17
Integrin Binding proteins	27	1
K homology RNA-binding domain, type I	25	9
Cytochrome C oxidase family	24	3
DNA methylation and histone deacetylation	38	10
Heat shock proteins	81	20
Ets transcription factor family	28	5
High Mobility Group proteins	24	2
Immediate early/regulator of G-protein signalling family	25	5
Kallikrein protease family	16	5
Matrix metallopeptidase family	21	7
Genes implicated in stem cell regulation	63	12
TCA cycle genes	56	16
Forkhead transcription factor family	43	11
TP53 responsive genes	76	22
Ubiquitination pathway genes	63	21
Ubiquitin Ligases	72	36
DEAD Box proteins	60	25
Genes associated with TP53 and targets	47	16

Curated Gene Update

The following fully curated genes also received minor updates : APC, BRAF, CDKN2A, CTNNB1, EGFR, ERBB2, HRAS, KIT, KRAS, NOTCH1, NPM1, NRAS, PDGFRA, PTEN, PTPN11, RB1, WT1.

General Statistics for this Release

Experiments	455765
Tumours	204457
Mutant Samples	41259
Mutations	43021
Unique Mutations	8122
Papers curated	4426
Genes	2671

COSMIC v27 released

This months release of COSMIC comprises upgrades to both the web site (which now allows searching by gene/sample name or keyword) and data, with new CGP resequencing studies and curated genes. COSMIC now contains data on over 200,000 tumour samples and 400,000 individual experiments. Of these 202109 tumours, 40331 were found to contain one or more mutations (19.9%).

CGP Resequencing Studies

Two new studies examine our pilot data set comprising 40 cancer celllines that have a matched normal cell line, allowing all of the mutations to be confirmed as somatic.

Notch signalling proteins

This group of proteins comprise the Notch receptors and other proteins which are involved in Notch signalling. The Notch signalling pathway allows cells to communicate with each other and plays a crucial role in developmental regulation. NOTCH1 mutations have been associated with T-cell acute lymphoblastic leukaemia.

Phosphatidylinositol metabolism

This gene set includes proteins which control the synthesis and turnover of phosphatidylinositol which is synthesised in the endoplasmic reticulum before translocating to cytosolic membrane surfaces where it plays an important role in many cellular processes including cell signalling. Mutations in the phosphatidylinositol-3-kinase PIK3CA and the lipid phosphatase PTEN are associated with many types of cancer.

Literature Curation

STK11 (LKB1)

STK11 is a tumour suppressor, physically associating with p53 to effect growth suppression via p53-dependent apoptosis pathways; restoring gene activity into cancer cell lines defective for its expression results in a G1 cell cycle arrest. It has been identified as the cause of Peutz-Jeghers syndrome, an autosomal dominant disorder inducing an increased risk of melanocytic macules, gastrointestinal polyps and various neoplasms.

STK11 Statistics

Samples	2344
Mutations	92
Unique Sequence Changes	63

WT1

Wilms tumour is a solid cancer usually occurring in childhood, caused by malignant transformation of renal stem cells retaining embryonic differentiation potential. Several tumour suppressor genes have been associated with the development of WT, most classically the WT1 zinc finger DNA binding protein located at chromosome 11p13. A number of isoforms of the transcription factor WT1 exist, unusually exerting control over expression of target genes during both their transcription and splicing.

WT1 Statistics

Samples	1710
Mutations	106
Unique Sequence Changes	68

Website Upgrades

Search Facility

A major update to the COSMIC website this month is the Exalead search facility, allowing for easier navigation of the site. In the 'Text Search' field on the home page, you can search for a gene name or accession number, a sample name or id, or a tumour primary site or sub-site. There is a help page for more advanced searches, which can be accessed by clicking on the question mark in the search box, or the help button in the sidebar.

General Statistics for this release

Experiments	408164
Tumours	202109
Mutant Samples	40331
Mutations	42057
Unique Mutations	7736
Papers curated	4348
Genes	1638

COSMIC third anniversary release (v26)

This release comprises a significant increase in the number of CGP resequencing studies. The five new studies all examine our pilot sample set comprising 40 cancer cell lines that all have a matched normal cell line, allowing all of the mutations to be confirmed as somatic.

Nuclear receptors and cofactors

A related but diverse array of transcription factors interacting with a wide range of coregulatory proteins to form a complex network of multicomponent assemblies serving as coactivators or corepressors of transcription.

SCF and APC cell cycle control complex components

Skp1-cullin-F-box-protein complex (SCF) and the anaphase-promoting complex/cyclosome (APC) are ubiquitination complexes regulating progression through the cell cycle.

Nucleocytoplasmic transport components

Factors involved in both import and export of proteins from the nucleus, including nuclear pore components.

Human homologues of putative target "cancer" genes from transposon screens in the mouse

Human orthologues of genes targeted by insertions in transposon insertion screens for cancer genes in the mouse.

Protein Tyrosine Phosphatases (PTP)

Critical regulators of signal transduction, effecting the reversible phosphorylation of tyrosine residues in cell signalling proteins.

Curated Gene Update

The following fully curated genes also received minor updates : BRAF, CDKN2A, EGFR, ERBB2, FLT3, KIT, KRAS, PDGFRA, PTEN, PTPN11.

General Statistics for this release

Experiments	394675
Tumours	194928
Mutant Samples	39520
Mutations	41228
Unique Mutations	7505
Papers curated	4180
Genes	1516

COSMIC v25 released

This month's COSMIC release comprises significant updates to CGP resequencing studies and curation of the scientific literature.

Update to CGP Resequencing Studies

The six non-kinase CGP resequencing studies have received substantial updates to the number of genes included and the number of mutations found (the kinase studies were updated in November 2006). Fifty two new genes have been added to the DNA repair study, together with three in the Apoptosis and two in the GAP-GEF studies. The number of mutations discovered in each of the six studies has increased as shown below:

Study	Mutation Count
	v24	v25
Inositol Polyphosphate Phosphatases	8	12
Heterotrimeric G-Proteins	5	6
DNA repair genes	114	194
Apoptosis genes	38	82
Small monomeric GTPases	8	28
GAP-GEF genes	48	91

Literature Curation

In addition to the CGP resequencing studies, significant updates have been made to those genes which have received complete scientific literature curation. Three genes have been extensively updated, BRAF (19.1%, increased to 19224 samples), JAK2 (25.1%, increased to 11190 samples) and NOTCH1(75.4%, increased to 488 samples), whilst eighteen other genes have received minor updates (less than 10% increase in sample number): ABL1, APC, CDKN2A, CEBPA, CTNNB1, EGFR, ERBB2, FLT3, KRAS, MET, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RET, SRC, VHL.

General Statistics for this release

Experiments	387254
Tumours	193513
Mutant Samples	39003
Mutations	40672
Unique Mutations	7272
Papers curated	4082
Genes	1398

COSMIC v24 released

This months release of Cosmic includes the curation of NPM1 and CDH1.

Curation details for NMP1

NPM1 (Nucleophosmin), is a nucleocytoplasmic shuttling protein andcritical regulator of TP53. Frequent mutations have been found in bothchildhood and adult AML. 20 papers have been manually curated for thisgene resulting in the addition of 45 unique mutations (exon 12).

NPM1 statistics

Samples	3870
Experiments	3875
Mutants	1171
Papers	20
Unique Mutations	45

Curation details for CDH1

CDH1 (E-cadherin), is a calcium ion-dependent cell adhesion moleculewith loss of function of this gene implicated in cancer invasion andmetastasis. In particular, somatic mutations of this gene have beenreported in gastric and lobular breast cancer. 181 mutations have beenadded to Cosmic for this gene from the curation of 46 papers.

CDH1 statistics

Samples	1958
Experiments	1970
Mutants	205
Papers	46
Unique Mutations	181

General Statistics for this release

Experiments	380741
Tumours	190358
Mutant Samples	38206
Mutations	39839
Unique Mutations	7032
Papers curated	4023
Genes	1343

COSMIC v23 released

This months release of Cosmic includes a major update to the protein kinase screens.

Protein Kinase Somatic Data Information

The Cancer Genome Project is pleased to release the full set of proteinkinase somatic mutation data resulting from the screening of over 200human cancers through the full set of 518 annotated genes. Over 1000mutations have been identified in a combined total of 247 megabasessequenced. This dataset is intended to serve as a catalyst for furtherbiological investigation of mutated kinases and pathways, hopefullyleading to new insights and therapeutic opportunities in human cancer.

http://www.sanger.ac.uk/genetics/CGP/Studies/Kinases/

Copy number data update

Oligo array CGH data (using the Affymetrix 10K SNP array) for a further233 cancer cell lines and 70 primary tumours has been made availableincreasing the total available from 834 to 1136 samples.

General Statistics for this release

Experiments	374169
Tumours	184092
Mutant Samples	36252
Mutations	37857
Unique Mutations	6758
Papers curated	3945
Genes	1342

COSMIC v22 released

This months release of Cosmic includes the curation from the scientific literature of the APC oncogene and information on the similarity between cell lines is now recorded and displayed in Cosmic.

Curation of APC literature

Mutations in the APC gene are one of the initiating events in colorectal tumorigenesis, both familial and sporadic. Our curation confirms that the majority of mutations occur in the central portion of the gene (the mutation cluster region, 'MCR') where mutations are associated with the most severe phenotype of huge numbers of polyps at a young age, often with extracolonic manifestations. Mutations outside the MCR cause a much milder and late onset phenotype, generating few polyps. We curated 206 papers for APC, finding 1420 mutated samples out of 7115 (almost 20%). As expected, there were no major hotspots; the most frequent mutation was p.R1450*, found in 87 samples (6%).

Web site

On the web site, we have begun to include information in Cosmic on samples found to be significantly similar by their genotype as assessed using Affymetrix SNP arrays. To date, 241 cell lines have been found to have genotypes which are greater than 80% identical with at least one other. This data is now displayed in the Cosmic Sample page under the heading of "Other Cancer Samples from the Same Individual"; here is an example: http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=sample&id=687448

General Statistics for this release

Experiments	290332
Tumours	173929
Mutant Samples	32891
Mutations	34390
Papers curated	3781
Genes	1342

COSMIC v21 released

This months release of Cosmic includes major updates to the Cancer CellLine Project and microsatellite instability status data sets. In addition,published somatic mutation data from two additional genes, MPL andFGFR1, have been added to Cosmic.

Cancer Cell Line Project Major Update

The Cancer Cell Line Project aims to systematically screen a large panel ofcancer cell lines for mutations in known cancer genes, thus empoweringthese cell lines as biological reagents for further work in anti-canceragent development and further work on cancer molecular and cellularbiology.

For this release of Cosmic, a further 137 cell lines have been added tothe working set and 78 duplicate cell lines have been removed. This bringsthe total number of samples to 787. A further 98 mutations have also beenadded (See: http://www.sanger.ac.uk/genetics/CGP/CellLines/).

Statistics for the CGP Cancer Cell Line Project

Experiments	12887
Samples	787
Mutant samples	1087
Mutations	1144
Unique Mutations	3519
Genes	21

MSI Data Update

The microsatellite instability (MSI) status for CGP samples under studyhas been updated, bringing the total number of samples with MSI statusto 1,530. (See:-http://www.sanger.ac.uk/genetics/CGP/MSI/msi_page.shtml).

Curation of MPL and FGFR1

Somatic mutations reported in the published scientific literature forthe FGFR1 and MPL genes has now been added to Cosmic.
MPL-http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=MPL
FGFR1-http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=FGFR1

General Statistics for this release

Experiments	278786
Tumours	164905
Mutant samples	30566
Mutations	31933
Papers Curated	3611
Genes	1339

COSMIC v20 released

This months release includes NCI-60 updates and mutation data from the scientificliterature for VHL.

NCI-60 update

The CGP is pleased to release mutation data for 24 known cancer genes on theNCI-60 series of cancer cell lines. These data should allow for greaterpower in interpretation of biological data using the lines as well asproviding a genetic framework for evaluating response to the largeseries of compounds screened against this reference cell line set.

Microsatellite instability

Microsatellite instability occurs due to a defect in mismatch repair.This is usually a result of inactivation of MSH2, MLH1 or MSH6 due to a mutation or to reduced expression associated with promoter methylation. Analysis of microsatellite instability was carried out using the BAT markers as described by Rodriguez-Bigas et al. All samples were screened using the markers BAT25, BAT26, D5S346, D2S123 and D17S250.Details of this, when available, are posted on the sample overview page. An example of which can be seen at http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=sample&id=905950

Curation of VHL

VHL mutation data from the literature is now available. We have curated 93 paperscovering 3412 experiments. These experiments used 3386 samples, in which 879mutations were recorded.

General Statistics for this release

Experiments	270623
Tumours	160594
Mutant samples	29154
Mutations	30439
Papers curated	3519
Genes	1338

COSMIC v19 released

This month's release of COSMIC includes the Cancer Genome Project screen of the GAP-GEF gene set and new information displays.

GAP-GEF Screen

This gene set, consisting of 173 genes, is comprised of proteins thatfunction to regulate the activity of proteins with GTPase activities.GTPase activating proteins (GAPs) promote hydrolysis of GTP-GDP. Guaninenucleotide exchange factors (GEFs) promote GDP/GTP exchange. Bothclasses modulate the function of the small monomeric GTPases (includingthe RAS oncogene family) and other key signalling proteins that use theconversion of GTP-GDP as a molecular switch to regulate function. Thissystem of GTPase/GAP/GEFs regulates a wide variety of cellular processesincluding growth, differentiation, survival and motility.

Web Improvements

Zygosity and somatic/germline status information are now available formutations in COSMIC, CGP Resequencing and Cancer Cell Project websites.The somatic/germline status is listed on the sample detail page and theexport function with the following statuses:-

• Not specified
• Confirmed somatic mutant
• Reported elsewhere as a somatic variant
• Confirmed germline variant
• Reported elsewhere as a germline variant
• Variant of unknown origin

Zygosity information is available on the mutation detail page with thefollowing statuses:-

• Unknown
• Homozygous
• Heterozygous

General Statistics for this release

Experiments	264296
Tumours	155902
Mutant samples	27732
Mutations	28859
Papers curated	3419
Genes	1337

COSMIC v18 released

The CGP Resequencing Studies Website is released this month, which will actas a repository for data from CGP resequencing efforts to identify novelsomatic mutations in human cancer. The pages have their own distinctive redcolour scheme to denote this. Prior data on sets of genes/samplessystematically screened for mutations were previously integrated into the "blue"COSMIC pages. This will continue with data now being submitted,prepublication, to and held on the new site. This will allow users tobrowse, search and evaluate these data more effectively. The web resourcesthat are now available are detailed below:-

• COSMIC (Blue): All data screened from literature and CGP based projects.
• CGP Resequencing Studies (Red): Somatic mutations from systematic large scale resequencing of genes in human cancers.
• CGP Cancer Cell Line Project (Green): Resequencing of known cancer genes and other analyses of human cancer cell lines.

Curation of PTCH

37 papers from the scientific literature have been curated for the PTCH gene in this release. Adding an additional 897 experiments and 168 mutations.

General Statistics for this release (COSMIC)

Experiments	254544
Tumours	153528
Mutant samples	27426
Mutations	28534
Papers curated	3393
Genes	1176

COSMIC DAS track

Ensembl has recently moved to the NCBI 36 assembly of the human genome whilst COSMIC genes and mutations are currently mapped to build 35. This has caused some disparity with the COSMIC DAS track. Therefore we suggest only using the cosmic DAS track on the most recent ensembl archive site(http://feb2006.archive.ensembl.org/index.html).Provided below is a link that will open the appropriate website with the DAS source attached:

http://feb2006.archive.ensembl.org/Homo_sapiens/contigview?conf_script=contigview;c=7:139949999.5:1;w=200000;h=7;add_das_source=(name=COSMIC+url=http://das.ensembl.org/das+dsn=cosmic_ncbi_35+type=ensembl_location+color=blue+strand=b+labelflag=n+stylesheet=y+group=n+depth=0+score=n+active=1)

Cosmic v17 release

This month's release of COSMIC includes the Cancer Genome Project screen ofsmall monomeric GTPases and mutation data from the scientific literature for MADH4.

CGP Small Monomeric GTPase Screen

The small monomeric GTPases function as key molecular switches impacting a large variety of cellular functions such as motility, cell signalling, transcription and the binding, hydrolysis andexchange of GTP/GDP. The RAS subfamily (HRAS, NRAS, KRAS) of small monomeric GTPases were amongst the first identified human oncogenes and are mutationally activated in a wide variety of human cancers.

Curation of MADH4

70 papers from the scientific literature have been curated for the MADH4gene in this release. Adding an additional 2275 experiments and 259 mutations.

Gene Updates

Further data from the scientific literature for 9 genes, including KRAS and NRAS, has been added for this release. A detailed breakdown for each gene can be seen below.

Gene Name	Additional experiments	Additional mutations
CDKN2A	668	71
CTNNB1	140	8
EGFR	150	4
ERBB2	84	1
HRAS	54	1
KRAS	3050	647
NRAS	1611	203
PTEN	37	7
PTPN11	309	17

General Statistics for this release

Experiments	249331
Tumours	149251
Mutant samples	26574
Mutations	27637
Papers curated	3324
Genes	1175

COSMIC v16 released

Released for March are data from a kinase domain screen of malignantgliomas. These data cover approximately 400kb of sequence in each of 9tumours, including data from recurrent/resistant tumours.

We have recently completed a screen for somatic mutations of the kinasedomain encoding exons of the entire protein kinase family in a series ofhuman malignant gliomas. The results are presented in this release ofCOSMIC. No commonly mutated kinase domain was found in these studies.However, as is the case with our other work in this area, deepsequencing data from human tumours is informative about the processesthat have contributed to oncogenesis in the patient. Two gliomasrecurrent after temozolomide (alkylator) chemotherapy, but not a thirdrecurrent after XRT alone, had the highest mutation prevalence of anytumours we have analysed to date. These data suggests a link betweenmutation prevalence and recurrent/resistant brain tumours treated withalkylator chemotherapy.

Statistics

Experiments	235213
Tumours	143427
Mutant samples	25360
Mutations	26388
Papers curated	3207
Genes	1035

A COSMIC Expansion

The Catalogue Of Somatic Mutations In Cancer is two years old and has mutation data for over 1,000 genes, curated from over 3,000 published papers and unpublished data from the Cancer Genome Project.

The original aim of COSMIC continues with the curation of somatic mutation information from the literature for known cancer genes. During 2005 data for 9 genes was collected; ABL1, CDKN2A, EGFR, GATA1, JAK2, MSH6, NOTCH1, PTPN11 and SMO. In addition to this, genes that were curated in 2004 were updated as new data was published.

The number of genes in COSMIC expanded rapidly when the Cancer Genome Project at the Wellcome Trust Sanger Institute published 3 studies of somatic mutations in the protein kinase gene family (518 genes in total). This data provides a unique insight to the somatic mutations in breast, lung and testicular cancers.

More recently the Cancer Genome Project has been submitting unpublished somatic mutation data to COSMIC (link). The data comes from genes involved in apoptosis, DNA repair, maintenance and metabolism and the Inositol Polyphosphate Phosphatase and Heterotrimeric G-Protein families.

In another new departure the COSMIC software was used to create a new web site the Cancer Cell Line Project. This separatesite, with it's own 'mint' colour scheme, contains the results from the sequence analysis of 14 known cancer genes in over 700 cancer cell lines. Initial sequence data for 4 genes analysed in the NCI-60 is also available. This work is in progress and more results will be posted in the coming months. What is more, the number of genes in this project will continue to increase; providing genetic data for this wide set of cancer cell lines.

There have been many enhancements to the web site over the past 12 months. A tissue overview provides a summary of mutations reported in a selected tissue. New pages were created to show more details of mutations and samples and give greater depth to the data. There are also links to other data such as genome copy number information.

COSMIC has been summarised in The British Journal of Cancer (Forbes et al, 2006).

This month sees the update of; BRAF, CDKN2A, EGFR, ERBB2, HRAS, KRAS, NRAS, PTEN, PTPN11 and SMARCB1. In addition the Cancer Genome Project has submitted unpublished data for genes involved in apoptosis.

There are plans to continue the development of COSMIC in terms of data content and data presentation. We are always happy to receive feedback and suggestions (email: cosmic@sanger.ac.uk).

Statistics

Experiments	228,669
Tumours	142,569
Mutant samples	25,176
Mutations	26,194
Papers curated	3,013
Genes	1,035

COSMIC v14 released

The COSMIC team is proud to announce the release of COSMIC-14 with data forCDKN2A(p16) and more unpublished data from the CGP.

DNA REPAIR, MAINTENANCE AND METABOLISM

The Cancer Genome Project has released further unpublished somatic mutation data from a screen of 41 cancer cell lines. The 302 genes in this release are involved or associated with DNA repair, maintenance and metabolism. The genes can be viewedtogether or in 5 subgroups; Telomerase Complex, SWI/SNF, DNA replication,Nucleotide Metabolism and DNA Damage Response and Repair. In total 119 somatic mutations were identified in this study.

CURATION OF CDKN2A

CDKN2A (also known as p16) is a tumour suppressor. It induces cell cycle arrest byinhibiting the phosphorylation of Rb by the cyclin-dependent kinases CDK4 and CDK6.So far 453 papers have been curated for this gene with 2,591 mutations recordedfrom 16,883 samples.

STATISTICS

Experiments	219,037
Tumours	140,212
Mutant samples	24,817
Mutations	2,637
Papers curated	3,379
Genes	870

COSMIC v13 released

Somatic mutation data from new gene families

In a major new departure the Cancer Genome Project is proud to releasefurther somatic mutation data. The results from the sequencing of twogene families, Inositol Polyphosphate Phosphatases and HeterotrimericG-Proteins, have been added to the data for the Protein Kinase genes. This data willbe expanded in the future with the addition of further gene sets.

Updates to existing genes

Nine genes in COSMIC have been updated with further data; NRAS, RB1,ERBB2, HRAS, PTEN, TP53, KRAS, APC and CDKN2A

New DAS data source

The Cancer Genome Project is pleased to announce the release of a DASsource devoted to the genes and mutations within COSMIC. Using thissource you will be able to view the genes and mutations from COSMICwithin a genome browser or the DAS client of your choice.

All 587 genes in COSMIC are exported as features. Each of these featuresdisplays the genomic 'footprint', which encompasses both exonic andintronic sequence between the start and end points of the CDS sequence.A link is attached to each feature, providing a mechanism for the clientto link back directly to the gene entry on the COSMIC website.

In addition to the gene footprints, there are also a large number ofunique mutations. These are also displayed as features, with links backto the mutation summary page in COSMIC. The database currently holds2812 unique mutations, of which 1035 are currently exported. This subsetis comprised of all the single nucleotide substitutions. More complexmutations will be included, as the genomic coordinates are mapped.

The DAS source can be found at the following URI:

http://das.ensembl.org/das/cosmic_genomic

The easiest way to view this source is to place the following URI inyour browser:

http://www.sanger.ac.uk/turl/6d8

This will attach the DAS source and display some of the mutations foundin BRAF. Additional configuration can be performed on the track, byclicking on the track name. For more information, see the help pages onthe Ensembl website.

COSMIC statistics

Experiments	190,576
Tumours	124,381
Mutant samples	23,232
Mutations	2,228
Papers curated	2,812
Genes	587

COSMIC version 12 released

The November release of COSMIC has further data on 9 known cancer genes.

GENE UPDATES

The genes with additional data are; BRAF, PTEN, RB1, EGFR, TP53, CDKN2A,NRAS, KRAS and PIK3CA.

VERSION

We have implemented a versioning system for the data in COSMIC. Thecurrent release is version 12 with a plan to release a new version everymonth.

CANCER CELL LINE PROJECT.

There are additional mutations for the known cancer genes beingsequenced through the cancer cell lines. Notably there is data forhomozygous deletions in the CDKN2A gene.

COPY NUMBER DATA

The Cancer Genome Project has released more copy number data derivedfrom the analysis of cancer cell lines and primary tumours usingAffymetrix SNP microarrays. So far a total of 834 samples have beenanalysed consisting of 161 primary tumours and 673 cancer cell lines.This data is freely available from the CGP website. The primarytumours overlap with those being sequenced by the CGP while the cancercell lines include those being sequenced in the Cancer Cell LineProject.

COSMIC STATISTICS

Tumours 124,367

Experiments 188,529

Mutations 23,157

Papers 2,224

Genes 538

COSMIC Update

COSMIC has been updated with the addition of 2 new curated genes and new mutation descriptions.

MUTATION DESCRIPTIONS

COSMIC has adopted the Human Genome Variation Society sequence variation/mutation nomenclature for the bulk of the mutations in COSMIC. This represents a major upgrade with the aim of improving clarity and enables the listing of intronic variants for the first time.

GENE UPDATES

Two genes have further data in COMSIC; EGFR and PTEN.

PROTEIN KINASE MUTATIONS IN TESTICULAR CANCER

The sequence analysis of the protein kinase gene family in human testicular germ-cell tumours of adolescents and adults has been published. The mutation data from this work was previously available in COSMIC and is now joined by the published analysis of the data.

CANCER CELL LINE PROJECT

There are additional mutations from the screening of known cancer genes through an extensive set of cancer cell lines.

STATISTICS FOR COSMIC

Tumours	123,197
Experiments	186,181
Mutations	22,711
Papers	2,157
Genes	537

COSMIC Update

COSMIC has been updated with the addition of 3 new curated genes;MSH6, NOTCH1 and PTPN11.

There is a new member to the COSMIC family; theCancer CellLine Project. This portal uses the COSMIC code to serve mutationdata from the cancer cell lines being sequenced by the Cancer GenomeProject at the Wellcome Trust Sanger Institute. The cell line datais presented in the same style as the COSMIC data with a unique colourscheme. There are links to jump from the Cancer Cell Line Project pagesto view all of the data in COSMIC. At present there is data from 12known cancer genes in the Cancer Cell Line Project database.

In addition the results from the screen of all 518 protein kinasegenes in lung cancer, that were available in the previous release of COSMIC,have been published inCancer Research

.

NEW GENES IN COSMIC

• MSH6 - is a member of the MutS homolog family and is required for DNA mismatch specific binding. Almost one third of tumours of the large intestine have somatic mutations in this gene.
• NOTCH1 - has somatic small intragenic mutations in 60% of haematopoietic and lymphoid tumours.
• PTPN11 - is a nontransmembrane protein-tyrosine phosphatase. Approximately 6% of haematopoietic and lymphoid tumours have mutations in this gene.

COSMIC STATISTICS

Experiments	186014
Tumours	123039
Mutations	22598
References	2153
Genes	537