Abstract 62: COSMIC: Combining the world's knowledge of somatic mutation in human cancer

Abstract

Abstract COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://cancer.sanger.ac.uk) is the world's largest and most comprehensive online resource for exploring the impact of somatic mutations in human cancer. Live since 2004, the 71st release (Nov 2014) describes over 2 million mutations in more than 1 million tumour samples across most human genes. To emphasise depth of knowledge on known cancer genes, mutation information is curated manually from the scientific literature, allowing very precise definitions of disease types and clinically relevant patient details. Combination of over 20,000 published studies gives substantial resolution of how mutations and phenotypes relate in human cancer, providing insights into the stratification of populations and new diseases behind known biomarkers. Conversely, our curation of over 15,000 cancer genome studies emphasises knowledge breadth, driving discovery of new unrecognised cancer-driving hotspots and molecular targets. Our high-resolution curation approach is globally unique, giving substantial insight into molecular biomarkers in human oncology. For example, BRAF is well characterized in skin melanoma, transiently treatable with inhibitors such as Vemurafenib. It is also well known in colorectal cancer, which is largely non-responsive to BRAF inhibitors. COSMIC's unique approach demonstrates the impact of BRAF mutations in much less well-known cancers, for instance, Hairy Cell Leukaemia (89% of samples mutated) and Langerhans Cell Histiocytosis (49%), both of which respond remarkably well to BRAF inhibitors. Converse to skin melanoma, our curations suggest BRAF has a minimal role in Uveal melanoma (6% of Uveal tumors mutated for BRAF), with higher mutation rates in other genes (particularly GNA11, BAP1 and GNAQ), suggesting different mechanisms behind this disease. In addition to describing over two million coding point mutations across cancer, COSMIC also details more than six million non-coding mutations, 10,567 gene fusions, 61,232 genome rearrangements, 702,652 abnormal copy number segments, and more than 6 million abnormal expression variants. All these types of somatic mutation are annotated to both the human genome and each affected coding gene, then correlated across disease and mutation types. As increasing amounts of genetic data are gathered into COSMIC across human cancer, our annotations are beginning to emphasise events with a higher impact in cancer, highlighting the more functional coding mutations and major amplifications and deletions. This concept of high-impact data is being extended across the entire COSMIC system, much more strongly defining genes and mutations which drive oncogenesis. Citation Format: Simon A. Forbes, Dave Beare, Prasad Gunasekaran, Kenric Leung, Charambulos Boutselakis, Minjie Ding, Mingming Jia, Tisham De, Nidhi Bindal, Chai Yin Kok, Sally Bamford, Sari Ward, Charlotte Cole, Jon Teague, Michael R. Stratton, Peter J. Campbell. COSMIC: Combining the world's knowledge of somatic mutation in human cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 62. doi:10.1158/1538-7445.AM2015-62