As part of the V95 release we have focused on updating the expert-curated mutation data for rare cancers of the female genital tract and breast. This release has approximately 100 additional publications with mutation screening data in these diseases, including ovarian germ cell tumours, uterine Mullerian tumours and breast adenomyoepithelioma. We have also updated the classification of mucosal melanomas, including those associated with the female genital tract, to give details for the specific mucosal tissue.
V95 includes information about the resistance mutations in the FGFR2 and NT5C2 genes. We also have two new expert-curated genes, SDHA and TENT5C, which are associated with gastrointestinal stromal tumours and multiple myelomas respectively. Finally, we have focused on in-depth curation and updates of mutation data for the chromatin remodelling genes ARID1A, ARID1B, ARID2, andSMARCD1. More than 80 additional publications with mutation screening data in these genes are included in this release.
- New in-depth curation for cancer genes.
Cumulative data for each gene:
- SDHA - 16,291 samples, 163 mutations, 207 papers
- TENT5C- 16,838 samples, 148 mutations, 156 papers
- New resistance data for genes
Cumulative data for each gene:
- FGFR2 - 41,428 samples, 671 mutations, 793 papers
- NT5C2 - 4238 samples, 191 mutations, 116 papers
- In-depth focus on chromatin remodelling genes: ARID1A, ARID1B, ARID2, andSMARCD1.
- Disease focus on rare female genital tract and breast cancers
- Updated definition for mucosal melanoma
- Cancer Mutation Census data is also updated to align with latest COSMIC data (V95)
COSMIC statistics definitions
For transparency, we have recently changed our data definitions and created sub-categories to be clearer as to what the different mutation statistics mean for our users.
- Genomic variants (COSV)
Total number of unique variants recorded at the DNA/genomic level. Each COSV can be mapped to transcripts as a specific change. Multiple samples/papers with the same reported genetic change will all be reported under the same COSV. Because of multiple transcripts, a single COSV may fall into multiple sub-categories, hence the sum total of non-coding mutations, mutations with exons, and intronic/intragenic mutations will not equal total COSVs.
- Non-coding variants
Variants in the non-coding regions of DNA, including intergenic regions, regulatory regions and non-coding transcripts (pseudogenes, lncRNAs etc).
- Mutations within exons (coding variants)
Mutations that lie entirely or partly within the protein-coding regions (exons) of transcripts and give rise to a change in the Amino Acid sequence. This includes splice-site mutations
- Intronic + other intragenic mutations
Mutations within genes but located in introns, 5'UTR and 3'UTR regions; these mutations don't lead to known/predicted AA changes.
Where the mutations have come from. Can be patient samples, tissue samples, or cell line samples.
Number of papers our curators have studied in-depth inc. figures and supplementary data to derive COSMIC's data.
- Whole genome screen samples
Some WGS and WES data, and some gene-specific data from WGS.
Updates to T&Cs
We've updated our Terms & Conditions for Non-Commercial use of COSMIC Core data (including the Cell Lines Project, COSMIC-3D, and Mutational Signatures). Whether you're thinking of registering or a current user, it's vital you read these thoroughly.
Unless stated, these apply to all releases of COSMIC, including previous versions that you may have downloaded.
As part of this change, the following statement has been removed: 'If I now need a licence for my use of COSMIC data, instead of licensing I can use/continue to use an old unsupported version of COSMIC'. This means that you are not permitted to use old and unsupported versions of COSMIC.
We don't have capacity to support older versions of COSMIC. Our database is designed as a 'living tool' that is constantly evolving in line with the latest research and information. It's also important to note that old versions of COSMIC aren't kept up to date. As a result, many of the links are broken and the data isn't accurate. With this in mind, we hope you will understand the necessity for this change to our T&Cs.
Read the full T&Cs here
In-depth curation for chromatin remodelling genes
SWitch/Sucrose NonFermentable (SWI/SNF) is a chromatin remodelling complex which uses the energy of ATP hydrolysis to reposition nucleosomes, thereby regulating access to the DNA and modulating transcription and DNA replication/repair. Mutations involving subunits of the SWI/SNF complex are common in a wide range of cancers, occurring in approximately 20%, with ARID1A the most frequently mutated subunit. Those with the highest SWI/SNF mutation rates are ovarian clear cell carcinoma, clear cell renal cell carcinoma, hepatocellular carcinoma, gastric cancer, melanoma and pancreatic cancer.
Typical teratoid/rhabdoid tumour (AT/RT), a rare and highly aggressive malignancy of the central nervous system (CNS), is usually diagnosed in infancy or childhood and is most often characterised by loss of expression of theSMARCB1 gene product (INI1). However, an unusual case with retained expression of INI1 and without mutations identified in SMARCB1 is reported by Bookhout et al. (COSP49144) in an infant with thalamic AT/RT.
Johan et al. (COSP41712) report a series of cribriform neuroepithelial tumour (CRINET), a rare non-rhabdoid brain tumour showing cribriform growth pattern and SMARCB1 loss. They conclude that CRINET represents a SMARCB1-deficient non-rhabdoid tumour which shares molecular similarities with the AT/RT-TYR subgroup but has distinct histopathological features and favourable long-term outcome.
In renal medullary carcinoma, a highly aggressive type of renal cancer occurring in patients with sickle cell trait, loss of SMARCB1 expression has emerged as a key diagnostic feature and Jia et al. (COSP49139) demonstrate biallelic inactivation of SMARCB1 in the majority of their 20 cases.
In breast implant-associated anaplastic large cell lymphoma, a distinct entity which arises in the capsule surrounding textured saline or silicone breast implants, Quesada et al. (COSP49321) report a novel STAT3-JAK2 fusion as well as mutations or gene losses in several genes including SMARCB1.
Rooper et al. (COSP49118) find recurrent loss of SMARCA4 in sinonasal teratocarcinosarcoma (TSC), a rare and aggressive tumour with mixed teratomatous, carcinomatous and sarcomatous components. They suggest SMARCA4 inactivation may be the dominant genetic event in TCS and that this lesion is on a diagnostic spectrum with SMARCA4-deficient sinonasal carcinoma.
ARID1A is a key non-catalytic component in the SWI/SNF complex. It acts primarily as a tumour suppressor and is emerging as a potential therapeutic target. Hung et al. (COSP49190) study the spectrum of ARID1A genetic alterations in non-small cell lung carcinoma and assess the clinicopathological significance of these mutations and expression loss in these tumours.
Wu et al. (COSP49189) perform comprehensive genomic profiling in ovarian seromucinous borderline tumours, an uncommon ovarian epithelial neoplasm characterised by association with endometriosis, and find frequent somatic mutations in KRAS, PIK3CA and ARID1A.
The mutation profile at hotspots of ARID2 in oral squamous cell carcinoma patients from South India is examined by Das et al. (COSP49067) and Bala et al. (COSP48911) identify ARID2 as a novel tumour suppressor in early-onset sporadic rectal cancer. Both ARID1A and ARID2 are among the genes identified by Varaljai et al. (COSP49256) as drivers in intracranial metastases in malignant melanoma and as such are therapeutic targets.
Terminal Nucleotidyltransferase 5C (TENT5C), previously known as FAM46C, encodes a non-canonical poly(A) RNA polymerase. It is thought to enhance mRNA stability and gene expression, the main targets is mRNA which encodes ER-targeted proteins. Commonly found to be mutated in multiple myeloma, evidence suggests that TENT5C is a B-cell lineage-specific growth suppressor. Somatic mutations in multiple myeloma samples are recorded across the gene, most of these are substitutions.
SDHA (Succinate dehydrogenase complex flavoprotein subunit A) encodes a catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. Germline mutations associated with loss of heterozygosity in the tumour drive several cancer types. However, rarer second-hit somatic mutations, and occasionally double somatic mutations, are also reported. This is notably in SDHA expression-negative 'wild type' gastro-intestinal stromal tumours (GISTS) lacking KIT or PDGFRA mutations. Somatic mutations in other tumours, such as pituitary adenomas and paragangliomas, are also seen.
Extensive research has shown that targeting FGFRs with small molecule inhibitors halts receptor activation, downstream signalling, and results in tumour shrinkage. However, the efficacy of these inhibitors can be limited due to acquired mechanisms of chemotherapy drug resistance which impedes treatment and leads to tumour relapse.
v95 includes patient mutation data in which resistance to drug treatment is caused by point mutations in the FGFR2 gene. Cancers studied include; intrahepatic cholangiocarcinoma (iCCA), breast cancer, lung cancer and gastric cancer.
Multiple alternatively spliced isoforms of FGFR2 are known to exist, and mutations detailed here refer to amino acid numbering in the FGFR2-IIIb isoform, the FGFR transcript shown as canonical on the COSMIC website (ENST00000457416.6)
Genomic analysis shows an alteration in targetable oncogenes in almost 50% of cholangiocarcinoma patients with recurrent alteration in IDH1 and FGFR2. This occurs almost exclusively in patients with iCCA compared to extrahepatic.
FGFR2genomic alterations including activating point mutations, fusions, and rearrangements are known oncogenic drivers and provide a molecular signature to identify patients who may benefit from inhibition of FGFR2 tyrosine kinase activity.
Whilst second generation selective (ATP competitive) FGFR inhibitors such as BGJ398/infigratinib, Debio 1347, and pemigatinib/INCB054828 have been shown to increase the disease control rate, the rapid emergence of acquired drug resistance has been frequently observed. Goyal et al. (COSP42875) first described genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2fusion-positive iCCA. Through the analysis of pre- and post-progression ctDNA and tumour biopsies in three patients with FGFR2 fusion positive iCCAs treated with BGJ398, this study revealed the emergence of FGFR2 kinase domain mutations including a FGFR2 V565F gatekeeper mutation in all 3 patients. Goyal et al (COSP46683) followed this initial study with six FGFR2fusion-positive iCCA patients treated with FGFR kinase inhibitors BGJ398 and Debio 1347, and again found mutations in kinase domain residues - K660M, V565F/H, N550K/H/T, and L618V, plus M372I in the transmembrane domain. Consistent with these findings, four other investigators identified the emergence of similar FGFR2 kinase domain mutations in patients with FGFR2 fusion positive cholangiocarcinoma, who had initially responded to pemigatinib (Silverman et al, COSP49195 and Krook et al, COSP49205 ), BGJ398 (Krook et al, COSP47638) or an unspecified FGFR inhibitor (Kasi et al, COSP49199).
Mutations observed in these studies include M539L, N550K/H/T, V565F/H, E566A, L618V, K660M and K642R which result in increased receptor kinase activity. Structural modelling has suggested two ways in which these mutations confer resistance:
- Disruption of the "molecular brake" formed by the triad of residues N550, E566 and K642, thus stabilizing the active form of the kinase, or pushing the kinase into an active form.
- The gatekeeper mutation induces a steric clash, preventing drugs from entering the ATP-binding pocket.
Similar kinase domain gain of function FGFR2 activating mutations (and FGFR amplifications) were shown to be apparent in post-resistance samples of ER+ metastatic breast cancer after treatment with ER-directed therapy (Mao et al, COSP48455) and ER therapy with CDK4/6 inhibitors (palbociclib) (Formisano et al, COSP46556).
Apart from the emergence of secondary FGFR alterations, another challenge to the effectiveness of FGFR targeted therapies in patients is the occurrence of intra-tumoural and temporal heterogeneity. This is a major obstacle to the effectiveness of FGFR-targeted therapies in patients with liver cancers as shown by Goyal et al (COSP42875) and Kasi (COSP49199).
Bypass mechanisms also contribute to the development of drug resistance. Min Lau et al (COSP44344) demonstrated the emergence of a PKC dependent re-wiring mechanism to confer resistance to AZD4547 (second generation FGFR inhibitor) in FGFR2 amplified diffuse gastric cancer. The FGFR2 V565F gatekeeper mutation also emerged in a PDX model of the gastric cancer and overexpression during ex-vivo culture with AZD4547 which caused resistance to AZD4547 and cross resistance to infigratinib.
Next-generation covalent (irreversible) inhibitors, such as futibatinib (TAS 120), as a possible means to overcome or suppress resistance mutations, are studied by Goyal et al (COSP46683). They describe four patients with FGFR2 fusion positive cholangiocarcinoma who developed acquired resistance to infigratinib or Debio-1347 and subsequently responded to TAS-120, although gatekeeper resistance mutations were later found. A similar subsequent response to TAS-120 was shown using in vitro assays by Krooke et al. (COSP47638).
NT5C2 (5'-nucleotidase, cytosolic II) encodes a hydrolase that serves as an important role in cellular purine metabolism by acting primarily on inosine 5'-monophosphate and other purine nucleotides. Gain of function mutations in NT5C2 result in altered activating and autoregulatory switch-off mechanisms and a protein with increased nucleotidase activity. This drives resistance to thiopurine chemotherapy, such as 6-mercaptopurine, in relapsed acute lymphoblastic leukaemia (ALL). NT5C2 point mutations commonly occur at R39, R238, R367, and D407, and are frequently recurrent, with R367Q the most common relapse-associated NT5C2 mutation, accounting for 90% of mutant cases.
Please note that due to technical difficulties, resistance data for FGFR2 and NT5C2 are not showing on the website currently. All resistance mutations are available in the download files.
Female adnexal tumours of probable Wolffian origin (FATWO) are very rare gynaecological tumours of low malignant potential thought to derive from the mesonephric (Wolffian) remnants in the upper female genital tract. Most frequently they occur in the paraovarian region and occasionally within the ovary, fallopian tube or retroperitoneum. Mirkovic et al. (COSP45731) examine the molecular changes in FATWO to determine whether they are molecularly similar to mesonephric carcinoma. They find FATWO lacking mutations of KRAS/NRAS, which are characteristic of mesonephric carcinoma. Bennett et al. (COSP47213) also perform a molecular analysis of FATWO, finding few pathogenic mutations and suggesting this could be useful in the differential diagnosis of difficult FATWO cases showing similarity to more common ovarian and broad ligament lesions.
Wang et al. (COSP47834) report mutations in primary vaginal malignant melanoma, an extremely rare mucosal melanoma. In their cohort of 36 patients, NRAS mutations and PD-L1 expression are most prevalent, whereas the detection rate of KIT and TERT mutations is low. Patients with NRAS mutations have a poorer survival outcome compared with those with wild-type NRAS. For invasive melanomas arising from different anatomical sites in the lower female genital tract, Zarei et al. (COSP47239) observe the most common genetic alterations in KIT, TP53 and NF1.
Jung et al. (COSP48959) present whole exome sequencing results for gestational choriocarcinoma, a unique cancer of pregnant tissues. Hodroj et al. (COSP49095) report the molecular characterisation of ovarian yolk sac tumour, a rare malignant germ cell tumour, with mutations in KRAS, KIT and ARID1A which may be used as therapeutic targets. Frumovitz et al. (COSP48770) investigate mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer. Dundr et al. (COSP48465) highlight a case of ovarian mesonephric-like adenocarcinoma arising in serous borderline tumour.
Rare cancers of the breast include metaplastic breast cancer (MpBC), a predominantly triple negative breast cancer (TNBC) representing a histologically heterogeneous group of invasive carcinomas. MpBC is defined by differentiation of the neoplastic epithelium to a non-glandular component, such as squamous or mesenchymal e.g. spindle cell, osseous or chondroid. It is an aggressive form of breast cancer, with patients presenting at an advanced stage and it is often more resistant to conventional chemotherapy than other TNBC.
TP53 is the most frequently mutated gene in MpBC followed by PIK3CA, as shown by Afkhami et al. (COSP48792) who also report a PIK3CA-mutated case of MpBC with exceptional response to everolimus therapy. Vranic et al. (COSP48788) perform molecular profiling of spindle cell breast cancers and show they are characterised by targetable molecular alterations in the majority of cases. Reed et al. (COSP48795) report results of whole exome sequencing for MpBC, confirming previous reports of high frequency of TP53 mutations and presenting evidence for a significant enrichment of co-occurring mutations in PTEN, PIK3CA and TP53.
Breast adenomyoepithelioma, is an uncommon, biphasic tumour ranging from benign, to atypical in situ, and malignant, with the latter associated with carcinoma which can arise in the epithelial or myoepithelial component. Using whole exome and targeted massively parallel sequencing analysis Geyer et al. (COSP48780) demonstrate that oestrogen receptor-positive adenomyoepitheliomas display mutually exclusive PIK3CA or AKT1 activating mutations, while oestrogen receptor-negative tumours harbour highly recurrent codon Q61 HRAS hotspot mutations, which co-occur with PIK3CA or PIK3R1 mutations. This update also includes case reports of adenomyoepithelioma from Watanabe et al. (COSP48777) and Han et al. (COSP48782).
Total genomic variants (COSV) (+111,368)
Genomic non-coding variants (+68,362)
Genomic mutations within exons (coding variants)
Genomic mutations within intronic and other intragenic regions
Whole genome screen samples
Copy number variants
Gene expression variants
Differentially methylated CpGs