Nucleic Acids Research Advance Access published online on November 11, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp995
© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer
Simon A. Forbes,
Gurpreet Tang,
Nidhi Bindal,
Sally Bamford,
Elisabeth Dawson,
Charlotte Cole,
Chai Yin Kok,
Mingming Jia,
Rebecca Ewing,
Andrew Menzies,
Jon W. Teague,
Michael R. Stratton and
P. Andrew Futreal*
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
*To whom correspondence should be addressed. Tel: +122 349 4730; Email: paf{at}sanger.ac.uk
Received September 15, 2009. Revised October 15, 2009. Accepted October 16, 2009.
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ABSTRACT
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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.
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INTRODUCTION
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The Catalogue of Somatic Mutations in Cancer (COSMIC) database
is designed to annotate, hold, navigate and display the published
literature on somatic mutations in human cancer. Huge amounts
of information have been generated on this subject, but these
are difficult to examine collectively due to their format or
distribution. COSMIC collects all this detailed information
together in one place by precisely and exhaustively curating
the scientific literature, both for known cancer genes and large
systematic screens, and combines it with the large analyses
from the Cancer Genome Project (CGP) at the Wellcome Trust Sanger
Institute, UK. The website over this database is designed to
provide an easy interface to query this complex data, providing
graphical and tabulated aggregate views allowing detailed examinations
and summary analysis of mutation range and prevalence, both
from a gene and cancer type perspective. Most recently, whole-genome
sequencing results have been included, overviewed in a new circular
diagram with separate displays for navigation and viewing of
this new data.
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DATABASE CONTENT
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The data in COSMIC is derived from two sources. The literature
curation effort uses original publications as the data source
to maximize the precision of the data obtained, no indirect
curation of external databases has been performed. Genes are
highlighted for curation by their presence in the Cancer Gene
Census [(
1);
http://www.sanger.ac.uk/genetics/CGP/Census/],
focusing on these well-characterized genes and collecting large
quantities of information (for example, over 13 000 instances
of 105 unique sequence variants have been curated in KRAS).
Genes promoting cancer via point mutations have been primarily
targeted since they have a great impact in carcinogenesis and
a large quantity of information to confidently generate mutation
range and prevalence statistics. Cancer-promoting gene fusion
mutations are also being curated, as there are many more genes
promoting tumour growth via fusion events than point mutations
(
1). The literature curation process is largely manual, gradually
accumulating the quantity of data currently available over 9
years. As information is entered to COSMIC by dedicated trained
curators, software systems check each datapoint for accuracy
and integrity. Large systematic candidate gene screens are additionally
being curated in a semi-automated fashion, with initial interpretation
of large result sets automated, followed by further manual and
software checks. This should allow the inclusion of all somatic
mutations with potential impact in human cancer. These will
serve as a resource for whole cancer genome resequencing data.
All literature curation genes in COSMIC are updated each release
(six releases are scheduled per year) with data curated from
recent papers to present the most recent somatic mutation reports.
Additionally, COSMIC serves as the portal to access in-house somatic mutation screening data from the systematic resequencing studies undertaken by the CGP. Such information is now available for over 4000 genes screened. More recently, CGP data includes low coverage whole genome resequencing screens (2), utilizing next-generation sequencing technologies which can precisely identify genome-level rearrangements previously invisible in both karyotypic and candidate gene screen procedures. Each mutation found has been resequenced several times and examined by scientific staff for confident confirmation.
All annotations in COSMIC require the tumour sample to have a phenotypic classification. This comprises a description of where the tumour was found (e.g. lung) and its morphology (e.g. non-small cell lung cancer, NSCLC). Usually broken down into increasingly specialized definitions (e.g. skin, face, NS: malignant melanoma, lentigo maligna, NS), these allow the mutation data to be navigated at different levels. For instance it is useful to examine KRAS mutations from a broad primary site perspective; lung tumours show a very different mutation spectrum in this gene than large intestine cancers. However, examining Lentigo Maligna (a subclassification of melanoma) in isolation, shows mutations in only four genes, only two of which have significant frequencies (BRAF, NRAS). COSMIC’s phenotype definition system has been built for this purpose, allowing layered and very precise classification of each tumour. Rather than adhere to an existing standard of tumour classification, COSMIC has developed it from the ground up to be as useful as possible for this purpose. During curation the published classification for each tumour is recorded before being translated into COSMIC's; system. This system (not independently published) is described in further detail on COSMIC’s ‘additional info.’ page (http://www.sanger.ac.uk/genetics/CGP/cosmic/add_info/), including a listing of classification translations.
Each mutation recorded in COSMIC is given a unique identifier, a series of details and a single statement that precisely defines it (e.g. ‘c.1799T>A’; ‘p.V600E’; ‘chr2:g.140099605T>A’). This mutation ‘syntax’ is derived from the HGVS nomenclature recommendations (3). Coding domain annotations receive a ‘c.’ syntax, indicating the mutation is located on a cDNA CDS co-ordinate and a ‘p.’ syntax indicating an amino acid co-ordinate. Gene fusions receive an ‘r.’ syntax indicating the co-ordinate is relative to the gene pair’s mRNA co-ordinates, an important distinction as the UTR sequences can be significant in these novel products. Finally, mutations can also receive a ‘g.’ syntax indicating nucleotides on the golden path which are involved in the mutation. Details of these syntaxes are discussed at length at http://www.genomic.unimelb.edu.au/mdi/mutnomen/.
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DATA ACCESS
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The website is focused on presenting complex phenotype-specific
mutation data in an easily interpretable format, usually best
presented graphically. Initial entry into the system is usually
via selection of a gene or cancer tissue type (phenotype), either
using ‘browse by’ features where one is presented
with a list to choose from, or the ‘search’ box
where any text can be typed for a COSMIC database search. Whilst
browsing by gene is fairly straightforward, browsing by phenotype
can become complex, with multiple increasingly specialised phenotype
choices; for instance one can navigate to ‘lung’
only, or to the very specific ‘lung, right lower lobe;
carcinoma, adenocarcinoma’. Acceptable search terms include
not only gene names or phenotype terms, but also COSMIC database
IDs, or mutation description syntaxes (e.g. ‘p.V600E’).
Once a choice is made, summary information is presented with
mutation counts and frequencies; the gene summary page provides
a mutation spectrum map and many links to external resources;
the phenotype (tissue) summary page provides lists of mutated
genes. These pages lead into the histogram page, where most
examination of the data occurs. Mutations are graphically displayed
for the selected gene, as a histogram of single-base substitutions,
together with a map of insertions, deletions and complex replacement
mutations (
Figure 1). The histogram immediately shows the type
of cancer gene selected, easily identifiable by its mutation
signature.
Figure 1a shows BRAF, a gain-of-function oncogene,
requiring very specific sequence changes for oncogenic activation
[the missense mutation p.V600E represents 75% of all muations
found in this gene (
n mutated = 13 885)]. Conversely,
Figure 1b shows CDKN2A; cancer can only progress after this key tumour
suppressor gene is inactivated. As the histogram shows, this
can happen in a number of ways across the entire gene’s
length (
n mutated = 3262). Tabulated breakdowns of the data
are available under the graphic either by phenotype or sequence
change, and additional messages will appear if further fusion
mutation data is available for the gene. The histogram can display
mutations either by CDS or amino acid co-ordinates and, most
usefully, can be zoomed to scrutinize particular regions of
a gene more closely, with the tables below reflecting the details
in the zoomed region of the graphic. Additionally, once a gene
is being viewed, a phenotype can be specified (at any level
of detail) and both the graphic and table will be redrawn to
reflect the new parameters. In this way, the histogram page
can be used in a process of circular navigation, constantly
specializing from general to specific queries, gaining much
knowledge in the process. Links from this core page direct users
to summaries and further details of mutations and publications,
together with an export function, to output the information
onscreen in a spreadsheet format.
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Figure 1. The Histogram page forms the core of the COSMIC website, showing the mutation range for each gene selected. The frequencies of each single base substitution are shown in the histogram itself and each deletion, insertion and complex substitution are indicated below as triangles (deletions point down in blue, insertions point up in red) or bars (which indicate the length of sequence being replaced). Below the mutations, long single-colour bars indicate structural domains, providing links to external databases including Pfam and InterPro. Two histograms are shown to demonstrate the range of mutation distributions observed; (a) BRAF shows the classical gain-of-function spectrum, whereby very specific mutations are required to activate growth promotion, in this case most frequently a c.1799T>A substitution; (b) CDKN2A (p16) is a tumour suppressor gene, only allowing growth promotion when its activity is absent (‘loss-of-function’). Tumourigenic mutations only need to inactivate the gene, shown here as a range of mutations across the gene’s length, particularly including a large quantity of frame shifting insertions and deletions.
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Gene fusion mutations are indicated within the summary and histogram
pages, but in separate sections; if a gene is fused with another,
or a sample contains such a mutation, a separate indicator is
shown to direct the user to a summary page which overviews the
mutation frequencies and phenotypes associated with fusions
between the two selected genes, again with graphic and tabulated
displays. Fusions are defined by exon content, including UTR
exons which are significant in some fusion events, leading to
displays largely focused on defining the breakpoint with respect
to the nearest exon of each gene. The ‘r.’ mutation
syntax records not the breakpoint position, but the mRNA content
from each gene (including intronic or non-templated sequences
were appropriate).
Samples which have undergone whole-genome sequencing receive summary annotation in the form of a ‘circos’ diagram [Figure 2; (4)]. This is due to the quantity and complexity of the data collected by these studies, which includes extensive lists of coding and non-coding point mutations, copy number variations and genomic rearrangements. While most of this information can be displayed in linear tracks against standard karyotype ideograms, the non-linear nature of interchromosomal rearrangements is much more suited to a circular diagram, and COSMIC has now standardized on this format for whole-genome sequencing experiments. All known genotypic information for a sample is included in the diagram, regardless of its originating methodology. Forming a starting point for the investigation of these highly annotated samples, the ring of coding mutations provides links into the standard cosmic gene-centric views, the CNV track links into the CGP’s SNP array-based CGH site (http://www.sanger.ac.uk/cgi-bin/genetics/CGP/CGH_home.cgi) for further evaluation of copy number abnormalities, and the structural rearrangements link into a subsystem of pages to examine these in more detail.
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Figure 2. COSMIC has now standardized on Circos diagrams (4) to display genome-wide mutation analyses for a sample. Concentric rings display different data for the same sample, all located to the same genomic co-ordinates. On the outside of the circle, the chromosomes of the standard reference genome are coloured, numbered and appropriately scaled. Moving from the chromosome indicators to the centre of the circle, blue lines indicate the presence of coding point mutations in the coding domains of genes, a ring of histograms indicate the copy number of each genomic segment, red bars indicate the presence of small intra chromosomal rearrangements and green lines link chromosomes where large intra chromosomal rearrangements have been observed.
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The main COSMIC website (blue pages) overviews the whole database,
showing all curated information. However, within the larger
COSMIC websystem, multiple subdomains exist to navigate subprojects
independently, each colour-coded for easy recognition. A yellow
page (
http://www.sanger.ac.uk/genetics/CGP/Classic/) summarizes
the information curated from the scientific literature providing
summaries and links into COSMIC. Two entire websites, colour-coded
copies of the main cosmic system, overview the CGP's; contribution
to COSMIC. The CGP resequencing studies, focused candidate gene
screens sequencing large numbers of tumour samples through over
4000 genes are presented on a red COSMIC site (
http://www.sanger.ac.uk/genetics/CGP/Studies/).
In green, the cancer cell line project displays results of a
systematic characterization of the mutant genotypes of almost
800 well-known cancer cell lines (
http://www.sanger.ac.uk/genetics/CGP/CellLines/).
Particularly in the green website, mutations are only included
if they are known, or are highly likely to, have a significant
impact on the oncogenesis of the tumour examined; an additional
datasheet is available describing mutations of unknown significance
resulting from the cell line project.
While the COSMIC websites are geared toward easy graphical navigation, custom data mining and large-scale analysis often requires the data in a different format. For this purpose, the content of each release is summarized in a series of very large spreadsheets and placed on a dedicated FTP site (ftp://ftp.sanger.ac.uk/pub/CGP/cosmic) for downloading. For those needing to mine the full content of COSMIC, each release is also available as a relational database export in Oracle 10 format, but supporting this requires significant IT infrastructure.
COSMIC data is also available outside of the COSMIC system. Where possible, all co-ordinate data in COSMIC has been located on the human genome (i.e. genes, exons, mutations). This has allowed the integration of COSMIC data into the Ensembl genome browser (http://www.ensembl.org) via DAS [distributed annotation system, (5)]. Once COSMIC DAS tracks are turned on (either via Ensembl configuration or a link on the gene or mutation summary pages), COSMIC annotations for both genes and mutations can be examined in a genomic context (Figure 3). For the 62 main curated genes, mutation annotations in a peptide structure context (uniprot annotations) are also available as a DAS track. COSMIC DAS tracks are all available through http://www.dasregistry.org/. A much lengthier discussion of the data in COSMIC and its navigation is available as a Protocol document (6).
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Figure 3. COSMIC mutations are available in the Ensembl genome browser, into which all other genomic annotations can be combined. Each unique sequence change is separately indicated and in a genomic context, the coding bias of COSMIC’s data makes the annotations pile up over the exons. In this example, the first 15 rows of mutations in the PTEN gene is shown (reduced from 197 rows in Ensembl).
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FUTURE WORK
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As the complexity and scope of the data in COSMIC expands, more
tools are needed to mine the data and reference it to external
systems, and new systems are currently being built with this
in mind. Especially notable amongst these upgrades is a new
Biomart which will soon be available for COSMIC. Especially
designed for the mining of complex datasets, Biomart (
7) allows
the specification of any number of predicate sets, querying
the COSMIC database and returning the appropriate data in tabulated
form, with links back in to the COSMIC websystem where appropriate.
This has been designed to encompass the full scope of the published
COSMIC data rather than any subdomain. One of the strengths
of Biomart is its ability to federalize several independent
systems and query them together returning a coherent dataset
combined from all. Using the external database identifiers in
COSMIC already, the COSMIC biomart has been federated to Ensembl
to allow the retrieval of gene and genome annotations surrounding
regions of interest in cancer. Further federalization is possible
and we are examining other ways of integrating COSMIC with external
resources. It is expected this addition to COSMIC should be
available before the end of 2009.
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DISCUSSION
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COSMIC comprises a number of subtly different data domains.
Ninety percent of the mutation content adheres to the original
goal of curating the world’s literature on known cancer
genes. However, with the speed of DNA sequencing accelerate
rapidly, tumour analysis is becoming less focused on single
genes and it is not unusual to find studies which instead analyse
thousands. COSMIC has held CGP data from these screens for years
due to its use as a prepublication data release site for primary
tumour and cell line analyses. However, curating published systematic
screens has traditionally been more difficult due to the large
number of mutations and genes, and the lack of automatable informatic
access. In order to include these large-scale studies in COSMIC,
the curation systems have now been extended and the inclusion
of such data has begun with the release of the Sjoblom
et al. screen of breast and colorectal tumours in the full CCDS gene
set (
8). While the curation of point mutations in COSMIC is
an ongoing activity, the number of uncurated genes remaining
is rapidly reducing and has allowed a redirection of effort
to include oncogenic gene fusion events, with many more genes
involved than point mutations (
1). The genetic analysis of human
cancer has also begun to lose its coding-domain focus, with
full-genome resequencing of tumours now underway, generating
tens of thousands of mutations per sample, together with many
genomic rearrangements. These are now being released into COSMIC,
using the Circos diagram (
4) as a basis for summarizing genome-wide
data, particularly useful for presenting complex intra- and
inter-chromsosmal relationships. COSMIC will continue to curate
the world’s literature on somatic mutations in cancer,
but it will increasingly develop with the aim of displaying
and navigating data from whole cancer genome resequencing efforts.
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FUNDING
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Funding for open access charges: Wellcome Trust (grant reference
077012/Z/05/Z).
Conflict of interest statement. None declared.
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ACKNOWLEDGEMENTS
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The authors would like to acknowledge the Wellcome Trust for
support under grant reference 077012/Z/05/Z.
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REFERENCES
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- Campbell PJ, Stephens PJ, Pleasance ED, O'M;eara S, Li H, Santarius T, Stebbings LA, Leroy C, Edkins S, Hardy C, et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat. Genet. (2008) 40:722–729.[CrossRef][Web of Science][Medline]
- den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum. Mut. (2000) 15:7–12.[CrossRef][Web of Science][Medline]
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ABSTRACT
INTRODUCTION