GRCh38 · COSMIC v91

Overview

This section shows a general overview of information for the selected study (COSU identifier) or publication (COSP identifier). Studies may have been performed by the Sanger Institute Cancer Genome Project, or imported from the ICGC/TCGA. You can see more information on the help pages.

Reference
The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma.
Paper ID
COSP34281
Authors
Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D and Dermatologic Cooperative Oncology Group of Germany (DeCOG)
Affiliation
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; 2Department of Pathology, Massachusetts General Hospital Cancer Center, Boston; 3Broad Institute of MIT and Harvard; 4Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts; 5Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; 6German Cancer Consortium (DKTK); 7Department of Dermatology, Heidelberg University Hospital, Heidelberg; 8Department of Dermatology and Allergy, Hannover Medical School, Hannover; 9Department of Dermatology, University of Wuerzburg, Wuerzburg; 10Department of Dermatology, Venerology and Allergology, University of Schleswig-Holstein Hospital, Kiel; 11Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich; 12Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, Humboldt University, Berlin; 13Department of Dermatology, University of Mainz, Mainz; 14University Medical Center, University of Tübingen, Tübingen, Germany; 15Department of Genome Sciences, University of Washington, Seattle, Washington; 16Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; and 17First Department of Medicine, Medical School, University of Athens, Athens, Greece.
Journal
Cancer discovery, 2014;4(1):94-109
ISSN: 2159-8290
PMID: 24265153 (view at PubMed or Europe PMC)
Abstract
Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a "long tail" of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.
Paper Status
Curated
Genes Analysed
41742
Mutated Samples
78
Total No. of Samples
78

Mutation Matrix

This section shows the correlation plot between the top 20 genes and samples. There is more information in our help pages.

Genes

This table shows genes with mutations in the selected study/paper [more details]
Genes Mutated Samples
This table shows genes without mutations in the selected study/paper [more details]

Table Information

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This is a whole exome/systematic screen paper and the negatives for this paper should be inferred.

Variants

This tab shows genes with mutations in the selected study/paper [more details]

Genes Samples CDS Mutation AA Mutation

This tab shows non coding variant in the selected study/paper [more details]

Sample ID Sample Name ID NCV Annotation Zygosity Chromosome Genome start Genome stop Genome version Strand WT seq Mut seq FATHMM-MKL

This tab shows the gene expression and copy number variation data for this study [more details]

Table Information

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The table currently shows only high value (numeric) copy number data. Copy number segments are excluded if the total copy number and minor allele values are unknown.

Click here to include all copy number data. For more detailed information about copy number data and gain/loss definitions click here.

Sample Gene Expression Expr Level (Z-Score)

Over Expressed; Z-Score > 2.0

Under Expressed; Z-Score < -2.0

Normal; Z-Score within the range -2.0 to 2.0

CN Type Minor Allele Copy Number CN Segment Posn. Average Ploidy

1. N/A represents cases where the average ploidy value is not available( mostly ICGC samples). For some TCGA samples where the minor allele information is not available the average ploidy value could not be calculated.

2. For TCGA samples, the ASCAT algorithm was used to calculate the average ploidy.

3. For CGP samples, the PICNIC algorithm was used to calculate the average ploidy.

CNV

This table lists the samples in the selected study which have low/high methylation for each gene. [more details]

No data

This tab shows the fusion mutations observed in this sample [more details]

Gene Sample Name Id Sample(COSS) CDS Mutation Somatic status Zygosity Validated Type

Samples

This table shows mutated samples in the selected study/paper.

Sample Name Mutation Count

This table shows samples without mutations in the selected study/paper.

Non-Mutant Samples Sample Id (COSS)