Nidhi Bindal

COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer

COSMIC (http://www.sanger.ac.uk/cosmic) curates comprehensive information on somatic mutations in human cancer. Release v48 (July 2010) describes over 136 000 coding mutations in almost 542 000 tumour samples; of the 18 490 genes documented, 4803 (26%) have one or more mutations. Full scientific literature curations are available on 83 major cancer genes and 49 fusion gene pairs (19 new cancer genes and 30 new fusion pairs this year) and this number is continually increasing. Key amongst these is TP53, now available through a collaboration with the IARC p53 database. In addition to data from the Cancer Genome Project (CGP) at the Sanger Institute, UK, and The Cancer Genome Atlas project (TCGA), large systematic screens are also now curated. Major website upgrades now make these data much more mineable, with many new selection filters and graphics. A Biomart is now available allowing more automated data mining and integration with other biological databases. Annotation of genomic features has become a significant focus; COSMIC has begun curating full-genome resequencing experiments, developing new web pages, export formats and graphics styles. With all genomic information recently updated to GRCh37, COSMIC integrates many diverse types of mutation information and is making much closer links with Ensembl and other data resources.

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 (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer

The catalogue of Somatic Mutations in Cancer (COSMIC) (http://www.sanger.ac.uk/cosmic/) is the largest public resource for information on somatically acquired mutations in human cancer and is available freely without restrictions. Currently (v43, August 2009), COSMIC contains details of 1.5-million experiments performed through 13 423 genes in almost 370 000 tumours, describing over 90 000 individual mutations. Data are gathered from two sources, publications in the scientific literature, (v43 contains 7797 curated articles) and the full output of the genome-wide screens from the Cancer Genome Project (CGP) at the Sanger Institute, UK. Most of the world’s literature on point mutations in human cancer has now been curated into COSMIC and while this is continually updated, a greater emphasis on curating fusion gene mutations is driving the expansion of this information; over 2700 fusion gene mutations are now described. Whole-genome sequencing screens are now identifying large numbers of genomic rearrangements in cancer and COSMIC is now displaying details of these analyses also. Examination of COSMIC’s data is primarily web-driven, focused on providing mutation range and frequency statistics based upon a choice of gene and/or cancer phenotype. Graphical views provide easily interpretable summaries of large quantities of data, and export functions can provide precise details of user-selected data.

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.

Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells

Alterations in cancer genomes strongly influence clinical responses to treatment and in many instances are potent biomarkers for response to drugs. The Genomics of Drug Sensitivity in Cancer (GDSC) database (www.cancerRxgene.org) is the largest public resource for information on drug sensitivity in cancer cells and molecular markers of drug response. Data are freely available without restriction. GDSC currently contains drug sensitivity data for almost 75 000 experiments, describing response to 138 anticancer drugs across almost 700 cancer cell lines. To identify molecular markers of drug response, cell line drug sensitivity data are integrated with large genomic datasets obtained from the Catalogue of Somatic Mutations in Cancer database, including information on somatic mutations in cancer genes, gene amplification and deletion, tissue type and transcriptional data. Analysis of GDSC data is through a web portal focused on identifying molecular biomarkers of drug sensitivity based on queries of specific anticancer drugs or cancer genes. Graphical representations of the data are used throughout with links to related resources and all datasets are fully downloadable. GDSC provides a unique resource incorporating large drug sensitivity and genomic datasets to facilitate the discovery of new therapeutic biomarkers for cancer therapies.

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.

Abstract 93: COSMIC: The catalogue of somatic mutations in cancer receives full genome variant annotations

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://www.sanger.ac.uk/cosmic), is one of the most comprehensive web systems describing the impact of somatic mutations in human cancer. The information is sourced directly from the published scientific literature and the Cancer Genome Projects high throughput sequencing laboratories at the Wellcome Trust Sanger Institute UK (CGP), allowing a high data quality to be maintained. The v44 release (Nov. 2009) contained the curation of 8336 papers covering 71 known cancer genes by point mutation and 30 by gene fusion. The mutation data for all these genes is being maintained up-to-date and new genes are regularly added to this list. Additionally, 4871 genes and 2764 samples have been scrutinized by the CGP laboratories. As cancer genetics moves toward the analysis of whole genomes, COSMIC is being updated to handle and display these data and increase the functionality of the website. With the rapid development of sequencing technologies, the quantity of data that can be put into COSMIC is increasing fast. We have extended our curation process to include large exome-wide candidate gene screens, recently including the first such screen from Sjoblom et al (2006), and the first TCGA screen (2008) with other large scale screening datasets being curated. In addition, whole-genome screens are becoming available with many non-coding variations. From the CGP laboratories, we already have two low-coverage genome rearrangement screens in COSMIC and this will rapidly expand, beginning with the imminent release of rearrangement scans in a set of 24 breast tumours. High-coverage genome analyses are also beginning to become available; with full genome coverage, the majority of somatic mutations in a tumour can be identified and COSMIC is being prepared to receive and display this data. With the inclusion of these new data, the COSMIC website has evolved to allow more easy access to required data. New specialization filters are in place to provide methods to search for subsets of COSMIC data in the usual user-friendly web pages. More extensive investigations can be performed using the new COSMIC Biomart, an industry-standard data mining system allowing access through web pages or programmatic interfaces. As the inclusion of new genomic data accelerates and the systems through which it can be accessed evolve, COSMIC is well placed to remain a central resource in human cancer genetics. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 93.