Sari Ward

COSMIC: exploring the world's knowledge of somatic mutations in human cancer

COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://cancer.sanger.ac.uk) is the worlds largest and most comprehensive resource for exploring the impact of somatic mutations in human cancer. Our latest release (v70; Aug 2014) describes 2 002 811 coding point mutations in over one million tumor samples and across most human genes. To emphasize depth of knowledge on known cancer genes, mutation information is curated manually from the scientific literature, allowing very precise definitions of disease types and patient details. Combination of almost 20 000 published studies gives substantial resolution of how mutations and phenotypes relate in human cancer, providing insights into the stratification of mutations and biomarkers across cancer patient populations. Conversely, our curation of cancer genomes (over 12 000) emphasizes knowledge breadth, driving discovery of unrecognized cancer-driving hotspots and molecular targets. Our high-resolution curation approach is globally unique, giving substantial insight into molecular biomarkers in human oncology. In addition, COSMIC also details more than six million noncoding mutations, 10 534 gene fusions, 61 299 genome rearrangements, 695 504 abnormal copy number segments and 60 119 787 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.

COSMIC: somatic cancer genetics at high-resolution

COSMIC, the Catalogue of Somatic Mutations in Cancer (http://cancer.sanger.ac.uk) is a high-resolution resource for exploring targets and trends in the genetics of human cancer. Currently the broadest database of mutations in cancer, the information in COSMIC is curated by expert scientists, primarily by scrutinizing large numbers of scientific publications. Over 4 million coding mutations are described in v78 (September 2016), combining genome-wide sequencing results from 28 366 tumours with complete manual curation of 23 489 individual publications focused on 186 key genes and 286 key fusion pairs across all cancers. Molecular profiling of large tumour numbers has also allowed the annotation of more than 13 million non-coding mutations, 18 029 gene fusions, 187 429 genome rearrangements, 1 271 436 abnormal copy number segments, 9 175 462 abnormal expression variants and 7 879 142 differentially methylated CpG dinucleotides. COSMIC now details the genetics of drug resistance, novel somatic gene mutations which allow a tumour to evade therapeutic cancer drugs. Focusing initially on highly characterized drugs and genes, COSMIC v78 contains wide resistance mutation profiles across 20 drugs, detailing the recurrence of 301 unique resistance alleles across 1934 drug-resistant tumours. All information from the COSMIC database is available freely on the COSMIC website.

Data mining using the Catalogue of Somatic Mutations in Cancer BioMart

Catalogue of Somatic Mutations in Cancer (COSMIC) (http://www.sanger.ac.uk/cosmic) is a publicly available resource providing information on somatic mutations implicated in human cancer. Release v51 (January 2011) includes data from just over 19 000 genes, 161 787 coding mutations and 5573 gene fusions, described in more than 577 000 tumour samples. COSMICMart (COSMIC BioMart) provides a flexible way to mine these data and combine somatic mutations with other biological relevant data sets. This article describes the data available in COSMIC along with examples of how to successfully mine and integrate data sets using COSMICMart. Database URL: http://www.sanger.ac.uk/genetics/CGP/cosmic/biomart/martview/

COSMIC: High‐Resolution Cancer Genetics Using the Catalogue of Somatic Mutations in Cancer

COSMIC (http://cancer.sanger.ac.uk) is an expert‐curated database of somatic mutations in human cancer. Broad and comprehensive in scope, recent releases in 2016 describe over 4 million coding mutations across all human cancer disease types. Mutations are annotated across the entire genome, but expert curation is focused on over 400 key cancer genes. Now encompassing the majority of molecular mutation mechanisms in oncogenetics, COSMIC additionally describes 10 million non‐coding mutations, 1 million copy‐number aberrations, 9 million gene‐expression variants, and almost 8 million differentially methylated CpGs. This information combines a consistent interpretation of the data from the major cancer genome consortia and cancer genome literature with exhaustive hand curation of over 22,000 gene‐specific literature publications. This unit describes the graphical Web site in detail; alternative protocols overview other ways the entire database can be accessed, analyzed, and downloaded.

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

COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://cancer.sanger.ac.uk) is the world9s 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. COSMIC9s 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 world9s 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

Mining cancer genomes in COSMIC

COSMIC, The Catalogue Of Somatic Mutations In Cancer [http://cancer.sanger.ac.uk], is one of the largest repositories for somatic mutational events in human cancer. Data in COSMIC are curated from multiple sources, including from over 14,310 scientific publications, and are alongside data from the Cancer Genome Project at the Sanger Institute and global international consortia, such as The Cancer Genome Atlas and the International Cancer Genome Consortium. The COSMIC database currently accommodates over 300,000 mutations across 750,000 analyzed samples from 21,850 genes (COSMIC v60, July 2012). The Cancer Gene Census [http://cancer.sanger.ac.uk/cancergenome/projects/census/] is a list of almost 500 known cancer genes for which mutations have been identified as causally implicated in cancer. These genes are prioritized for full literature curation. The collection of whole exome and genome sequencing data in COSMIC continues to grow at a rapid pace. There are: 17,614 coding mutations, 84,747 non-coding variants in 396 whole genome screens; 121,619 coding mutations and 12,949 non-coding variants as result of 1,266 full exome sequencing; 3,512 structural mutations derived from 77 rearrangement screens. The data overview for each whole genome screen is presented using Circos, for example, the NCI-H209 Circos summary [http://cancer.sanger.ac.uk/cosmic/sample/overview?id=688013]. Analyzing information from whole genome sequencing can greatly enhance the chance of discovering novel genes implicated in human cancer. Unlike hot spot screening of gene regions where somatic mutations are most frequent, the use of whole genome data can identify all mutations in all genes, providing much more expansive annotations to recurrence analysis as used to discover new cancer genes. For instance, there are recurrent somatic mutations identified in genes, for example: SPOP in 19 prostate samples; SDK1 in 20 large-intestine samples. There are several ways to access and analyze the data in COSMIC. The website allows data viewing in a genomic context supported by GBrowse while maintaining our gene-centric perspective. New additional features include a filter for excluding identified SNPs from the 1000 Genomes Project, and displaying Pfam domains and links to biological pathways for selected genes. For mining a large dataset, COSMICmart (an instance of BioMart) is a tool for downloading user-customized datasets federated with external databases such as Ensembl and Uniprot. Moreover, we provide data export in multiple formats and Oracle database export through the FTP site [ftp://ftp.sanger.ac.uk/pub/CGP/cosmic]. In addition to somatic mutation data, we have integrated the data from the Genomics of Drug Sensitivity in Cancer Project [http://www.cancerrxgene.org], which is screening a wide range of anticancer therapeutics against over 1,000 genetically characterized human cancer cell lines. Data analysis is becoming increasingly challenging due to the rapid expansion in cancer genome sequencing capacity. COSMIC is a major cancer genetics resource aiming to help such investigations, providing a centralized somatic mutations database with a wide suite of tools for its examination.

The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers.

The Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC) is an expert-curated description of the genes driving human cancer that is used as a standard in cancer genetics across basic research, medical reporting and pharmaceutical development. After a major expansion and complete re-evaluation, the 2018 CGC describes in detail the effect of 719 cancer-driving genes. The recent expansion includes functional and mechanistic descriptions of how each gene contributes to disease generation in terms of the key cancer hallmarks and the impact of mutations on gene and protein function. These functional characteristics depict the extraordinary complexity of cancer biology and suggest multiple cancer-related functions for many genes, which are often highly tissue-dependent or tumour stage-dependent. The 2018 CGC encompasses a second tier, describing an expanding list of genes (currently 145) from more recent cancer studies that show supportive but less detailed indications of a role in cancer.This Review discusses the 2018 Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC), an expert-curated description of human cancer genes, which has recently been expanded to include functional descriptions of how each gene contributes to cancer.

Abstract 2599: COSMIC Cancer Gene Census: expert descriptions across genes in oncogenesis

The Cancer Gene Census is an ongoing effort to catalogue genes for which somatic mutations have been causally implicated in cancer. The Census comprises manually curated summaries of the most relevant information for cancer-driving genes and their somatic mutations and brings together the expertise of a dedicated curation team, cancer scientists and the comprehensive resources of the COSMIC database. Current research focuses on characterising the participation of 609 census genes in hallmarks of cancer and identification of additional genes involved in these biological traits primarily via altered expression, CNA or epigenetic changes. New overviews of cancer gene function focused on hallmarks of cancer pull together manually curated information on the function of proteins coded by cancer genes and summarises the data in simple graphical form. It presents a condensed overview of most relevant facts with quick access to the literature source, aiming to provide summary characteristics of a cancer gene, rather than a full monography, to avoid information overload. This functional characterisation enables the creation of lists of genes of interest focused on the particular role they play in the development of cancer, as well as aiming to identify the cellular functions affected by mutations in particular tumours, and help to choose right targets for targeted therapy or synthetic lethality experiments. The Census is available from the COSMIC website for online use or download at: http://cancer.sanger.ac.uk/census. Citation Format: Zbyslaw Sondka, Sally Bamford, Charlotte G. Cole, Elisabeth Dawson, Laura Ponting, Raymund Stefancsik, Sari A. Ward, John Tate, Peter J. Campbell, Simon A. Forbes. COSMIC Cancer Gene Census: expert descriptions across genes in oncogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2599. doi:10.1158/1538-7445.AM2017-2599

Abstract 5285: COSMIC: comprehensively exploring oncogenomics

COSMIC (http://cancer.sanger.ac.uk) is an expert-curated database of somatic mutations causing human cancer. Broad and comprehensive in scope, its 75th release (Nov 2015) describes over 3.7 million coding mutations across all human cancer disease types. Mutations are annotated across the entire genome, but expert curation is focused on almost 200 key cancer genes. Now encompassing the majority of molecular mutation mechanisms in oncogenetics, COSMIC additionally describes 10 million non-coding mutations, 1 million copy number aberrations, 9 million gene expression variants and almost 8 million differentially methylated CpG’s. This information combines a consistent interpretation of the data from the major cancer genome consortia and cancer genome literature, with hand-curation of over 22,000 gene-specific literature publications. With such a large volume of data, it is increasingly important to indicate which information is most significant. All mutations in COSMIC are now given a functional significance score, calculated using the FATHMM algorithm. In addition, a mutation can also be tagged as low-impact if they are described as a polymorphism in normal human genomes. All this information is available for selection and exploration in the COSMIC website (http://cancer.sanger.ac.uk), and for download via COSMIC Downloads (http://cancer.sanger.ac.uk/download). In addition to this broad database, the Cancer Gene Census (http://cancer.sanger.ac.uk/census) is a project within COSMIC aiming to identify and characterize all genes known to cause cancer, currently describing over 570 genes. This Census is now a priority focus of development, with a dedicated curator explicitly defining the range of genes driving cancer, including primary alleles and mechanisms and the diseases which are induced, with detailed supporting evidence. In addition to these analytical websites, expert-curated lists and now a GA4GH Beacon, COSMIC also hosts a full Oncology Genome Browser (http://cancer.sanger.ac.uk/genome). This fully-featured system allows the exploration of all cancer somatic mutation data collected in COSMIC alongside genomic annotations including coding genes, ncRNAs, SNPs and regulatory features. All data is vertically integrated, allowing exploration of how these many genetic mechanisms might promote oncogenesis, and how similar activating/inactivating mechanisms correlate. Amongst many interesting examples, there is a clear cluster of structural rearrangements immediately upstream of the BRD4 epigenetic modifier gene, affecting a region of multiple transcription control elements, and a substantial accumulation of abnormally hypermethylated CpG islands in the HOXA gene cluster on chromosome 7 coinciding with a group of HOTAIR and HOTTIP miRNAs. With multiple filters and selections available, these visualizations will increasingly support the exploration of how a variety of mutation mechanisms may act together to cause specific cancer diseases. Citation Format: Simon A. Forbes, Nidhi Bindal, David Beare, Sally Bamford, Charlotte G. Cole, Sari Ward, Kenric Leung, Chai Yin Kok, Mingming Jia, Tisham De, Zbyslaw Sondka, Michael R. Stratton, Peter J. Campbell. COSMIC: comprehensively exploring oncogenomics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5285.

Abstract 5326: COSMIC: Enhancing the world's knowledge of somatic mutations in human cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://cancer.sanger.ac.uk) is the worlds largest and most comprehensive online resource for exploring the impact of somatic mutations in human cancer. Now running for over 10 years, the 67th release (Oct 2013) describes 1592109 mutations in 947213 tumour samples across 25606 genes. This information is curated manually from the scientific literature, and automatically from genome resequencing consortium data portals. Full curation of the scientific literature provides in-depth understanding of the impact that each gene has in human cancer, and this has been achieved for 127 point-mutated cancer genes, and 185 fusion gene pairs. Curated genes are selected from the Cancer Gene Census (http://cancer.sanger.ac.uk/census), a listing of all genes with substantial evidence implicating them in cancer promotion, currently numbering 513 and updated frequently. The mutations discovered in the re-sequencing of over 8000 tumour genomes are now present in COSMIC (viewable in isolation from the genic curations, http://cancer.sanger.ac.uk/wgs). In addition, the Sanger has now fully exome sequenced 1015 common cancer cell lines, identifying 1146874 coding mutations annotated for functional significance, and this is available exclusively in COSMIC at (http://cancer.sanger.ac.uk/cell_lines). While COSMIC has focused on point mutations and gene fusions, many other mutation mechanisms cause oncogenesis and these are now being integrated. The 67th COSMIC release includes copy number mutations integrated into the database and major web page views. To allow easy graphical examination of this data, copy number information was reduced to ‘gain’ and ‘loss’ annotations for inclusion in histograms and tables, with much more precise detail available with a further click. Copy number data is available in detail for every gene in COSMIC, and also for every tissue. Exploring cancer via COSMIC’s Cancer Browser (http://cancer.sanger.ac.uk/cosmic/browse/tissue), results not just in a plot of the most mutated genes, but now also a circular genome plot summarizing the copy number gains and losses across all the samples from that tumour type, all explorable in more detail via clicks on the pictures. As the genomic data increases in COSMIC, it is becoming more important to qualitatively annotate the information, indicating which is more important or significant to oncogenesis. We are now building systems to better highlight known or putative functional mutations, improving the signal-to-noise ratio of cancer genome resequencing. Citation Format: C Boutselakis, S A. Forbes, P Gunasekaran, M Jia, D Beare, N Bindal, C Y. Kok, K Leung, D Minjie, R Shepherd, S Bamford, S Ward, C Cole, J W. Teague, M Stratton, P Campbell, U McDermott. COSMIC: Enhancing the worlds knowledge of somatic mutations in human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5326. doi:10.1158/1538-7445.AM2014-5326