cosmic is designed to gather , curate , organize and present the world s information on somatic mutations in cancer and make it freely available in a variety of useful ways , most easily accessible through its website ( http://www.sanger.ac.uk/cosmic ) . as previously described ( 1,2 ) ,
cosmic combines cancer mutation data manually curated from the scientific literature , with the output from the cancer genome project ( cgp ) at the sanger institute uk .
genes are selected for full literature curation using the cancer gene census ( http://www.sanger.ac.uk/genetics/cgp/census/ ) , with a focus on those mutated by small point mutations in the coding domains , and more recently including those mutated by gene fusion . in the age of whole cancer genome sequencing ,
it is now possible to describe the genome - wide somatic mutation content of a tumour sample , including structural rearrangements and non - coding variants .
cosmic is now integrating this information into the database , providing full coding and genomic variant annotations for samples , both from cgp laboratories and recent publications .
for years , the cosmic database has described somatic mutations in key cancer genes across many cancer samples , and , more recently , gene fusions and structural rearrangement annotations have been included .
much of the basic functionality of the system has been maintained as previously described ( 1,2 ) , including the nomenclature system for tumour phenotypes and the hgvs syntax for mutations . in the past year , full mutation details have been curated into cosmic for 19 new cancer genes , making a total of 83 fully curated and up - to - date cancer genes , the majority of which are point - mutated ; the number of curated fusion gene pairs has also doubled to 49 .
in addition to this , a major effort to curate significant external resources and publications into cosmic has enhanced the coverage of the database .
most importantly , the mutation spectrum of the key cancer gene tp53 is now included ; in collaboration with the curators at iarc ( 3 ) , the majority of the iarc p53 database r14 release is now available in cosmic .
in addition , all the somatic mutation annotations from the tcga large - scale cancer characterization project are now included ( 4 ) , as are those from a number of significant systematic candidate gene screen publications ( 57 ) . in total , more than 47  000 coding mutation annotations have been added to cosmic in the last year , together with over 53  000 non - coding mutations .
current contents of the database ( v48 , july 2010 ) are displayed in table 1 . 

table 1.total contents in v48 of the cosmic database , july 2010 releasecurated data typecurated data countexperiments2  760  220tumours541 
928mutations136  326references10  383genes18  490fusions4946structural variants2307whole cancer genomes29 total contents in v48 of the cosmic database , july 2010 release with the increasing genomic context in cosmic , the system has expanded to encompass the complete annotation of somatic mutations across whole genomes , including all coding and non - coding mutations , structural rearrangements and gene fusions .
links are also present into the conan system ( http://www.sanger.ac.uk/cgi-bin/genetics/cgp/cghviewer/cghhome.cgi ) for copy number variant annotations .
the fullest and most detailed genome annotations are from the cgp laboratories ( 8,9 ) , but in addition , curation of large - scale systematic candidate gene screens ( 5,6,7 ) and whole genome analyses ( 10 ) from the scientific literature has commenced .
the first 26 samples , mostly breast carcinoma tumours , represent low - coverage paired - end scans characterizing somatic structural rearrangements at basepair resolution ( 11 ) .
two samples ( malignant melanoma and small - cell lung carcinoma cell lines ) have undergone whole - genome resequencing , providing much more extensive annotations ( 8,9 ) .
point mutations and small insertions / deletions are described , several hundred in coding domains and many thousands either intronic or intergenic . including structural variants and cnvs ,
these samples are summarized in a more complex circos diagram , presenting rings describing point mutation types and impact on any coding domains ( figure 1 ) .
finally , mardis et al . ( 10 ) describe the full - genome resequencing of a single aml sample ( and subsequent characterization of a further cohort ) ; this is the first genome analysis to be curated from the literature .
all non - coding variants and structural rearrangements are described only in terms of grch37 co - ordinates , whilst coding mutations are described in genomic terms , together with co - ordinates in the cds and peptide they affect . 

figure 1.circos diagram summarizing the full somatic mutation content of cell line nci - h209 .
, the core displays the structural rearrangements ; intrachromosomal are in green , interchromosomal in purple .
the next ring out shows the chromosomal copy number in histogram form , with inner red patches indicating regions of loh .
further out , several rings of single base coding substitutions are shown ( black tiles show splice site mutations , red stop - gained , purple non - synonymous and grey synonymous changes ) .
the inner dark orange and outer light orange histograms represent non - coding mutations , relative frequencies of homozygous and heterozygous mutations , respectively . in the final ring before the chromosome indicators ,
, the core displays the structural rearrangements ; intrachromosomal are in green , interchromosomal in purple .
the next ring out shows the chromosomal copy number in histogram form , with inner red patches indicating regions of loh .
further out , several rings of single base coding substitutions are shown ( black tiles show splice site mutations , red stop - gained , purple non - synonymous and grey synonymous changes ) .
the inner dark orange and outer light orange histograms represent non - coding mutations , relative frequencies of homozygous and heterozygous mutations , respectively . in the final ring before the chromosome indicators ,
the cosmic website is available at http://www.sanger.ac.uk / cosmic/. while the ability to navigate the cosmic database by gene and tissue type has been maintained , it has evolved to become much more mineable .
the gene histogram page , which graphically summarizes the somatic mutations on the coding sequence of the gene ( e.g. figure 2 ) , still forms the core of the navigation system for the majority of the data .
multiple methods are now available for filtering the data , forming specialized queries . in each case , the image will be regenerated , and the mutation spectrum and tissue - specific frequencies will be recalculated for the selection chosen : ( i ) clicking on the graphic or inputting cds co - ordinates zooms into the required region of the gene ; ( ii ) clicking on the primary tissue type offers a method of selecting a specialized phenotype ; and ( iii ) in the left - side navigation bar ( left side of figure 2 ) , further filters are available including restrictions by mutation type ( substitution , deletion , etc . ; missense , nonsense , frameshift etc . ) , sample source ( cell line , primary tumour ) , somatic status ( was the mutation confirmed somatic or was the normal tissue not available ) and systematic screen ( were these results generated as part of a much larger genome - wide candidate gene screen or genome resequencing study ) .
simultaneously using multiple filters , it is possible to build up a very specific query focused on exact requirements of gene / phenotype and data content . expanding this selection process , we have begun generating summary diagrams in the form of pie charts which both overview the selected data and provide links into subsets by automating the selection process in one click .
initially available under the  distribution button on the histogram page are two such summaries ( figure 3 ) : the first provides a breakdown of mutation counts by mutation type and the second shows a breakdown of mutant samples by their source ( cell line , primary tumour or unknown ) . in each case , 
more details links provide options to regenerate the histogram page with the specified selection , or to view the full data in tabulated form , ready for export in spreadsheet format .
in addition to enabling mutation spectrum analyses at the gene level , cosmic has also begun providing spectrum analyses at the sample level . for samples with significant numbers of mutation data ,
a mutation spectrum histogram is available ( figure 4 ) to show summary nucleotide exchange frequencies from the sample s repertoire of coding mutations .
this can be found on the sample overview page , where multiple tabs facilitate the examination of many data types for each sample . 

the histogram shows relative frequencies of mutations ( y - axis ) across the cds of the gene ( x - axis ) . underneath the x - axis scale bar
are complex replacement mutations , followed by simple deletions ( blue triangles ) and insertions ( red triangles ) . under this , zoom options are available . on the left ,
figure 3.pie charts ( here showing the tp53 gene ) are increasingly used for summarization of complex spectrum data in cosmic .
the top graph ( a ) shows the breakdown of all observed mutations by type , and the lower ( b ) shows the breakdown of mutated samples by source .
the total number differs slightly due to some samples having more than one mutation , thus being counted once in ( b ) but twice or more in ( a ) . 

figure 4.mutation spectrum histogram for whole - genome - resequencing sample colo-829 , displaying the considerable overrepresentation of c : g > t : a events in its coding mutation repertoire , reflecting the characteristic signature of dna damage due to ultraviolet light exposure common in malignant melanoma . the gene histogram page for tp53 .
the histogram shows relative frequencies of mutations ( y - axis ) across the cds of the gene ( x - axis ) . underneath the x - axis scale bar
are complex replacement mutations , followed by simple deletions ( blue triangles ) and insertions ( red triangles ) . under this , zoom options are available . on the left ,
pie charts ( here showing the tp53 gene ) are increasingly used for summarization of complex spectrum data in cosmic .
the top graph ( a ) shows the breakdown of all observed mutations by type , and the lower ( b ) shows the breakdown of mutated samples by source .
the total number differs slightly due to some samples having more than one mutation , thus being counted once in ( b ) but twice or more in ( a ) .
mutation spectrum histogram for whole - genome - resequencing sample colo-829 , displaying the considerable overrepresentation of c : g > t : a events in its coding mutation repertoire , reflecting the characteristic signature of dna damage due to ultraviolet light exposure common in malignant melanoma .
while the website has been built to be as user friendly as possible , a new biomart ( 12 ) has been made available which emphasizes flexibility ( available at http://www.sanger.ac.uk/genetics/cgp/cosmic/biomart/martview/ ) .
this system provides all available selections on genes , tissues and mutations as pull - down menus and provides tabulated reports on the data selected which are again exportable in spreadsheet format for offline investigation .
an increasing emphasis is developing on resequencing of full cancer genomes and , in response , we have upgraded all our genomic co - ordinates to grch37 .
this has allowed us to begin integrating much more directly with the ensembl genome browser ( www.ensembl.org ) .
data on the 83 curated genes have been uploaded from cosmic into ensembl databases , and this has allowed the incorporation of cosmic data directly into the ensembl web pages , as 
these pages display the cosmic mutation in the local sequence context , with annotations on all ensembl transcripts for the gene .
also included are links to ensembl s genomeview websystem , providing views of the mutated gene with full genome annotations .
links back to cosmic have been carefully incorporated into the ensembl website to give more detailed and specialist views of the data .
initially released in august 2010 , the full cosmic data set is expected shortly after .
a number of other external projects have been receiving our support integrating cosmic data , including intogen ( http://www.intogen.org/home ) , uniprot ( http://www.ebi.ac.uk/uniprot ) and pfam ( http://pfam.sanger.ac.uk ) .
many more have used exports from the ftp site to extend existing systems ( e.g. cgwb ; https://cgwb.nci.nih.gov ) , or develop new ones , for example , as integration resources of selected data subsets ( e.g. canprovar ; http://bioinfo.vanderbilt.edu/canprovar ) .
further external projects have integrated cosmic s search feature into their systems , interpreting results of remote search queries for local examination , with links back into the cosmic website ( e.g. onix ; http://www.ncri-onix.org.uk ) .
a stable identifier system has been developed for cosmic somatic mutations to allow external databases to easily link back to the appropriate cosmic record .
cosm i d ( cosmic somatic mutation identifier ) which will remain stable between releases of cosmic .
ensembl is the first external database to successfully use the cosm i d and we ask other database to maintain this identifier when using cosmic annotated mutations .
an increasing emphasis is developing on resequencing of full cancer genomes and , in response , we have upgraded all our genomic co - ordinates to grch37 .
this has allowed us to begin integrating much more directly with the ensembl genome browser ( www.ensembl.org ) .
data on the 83 curated genes have been uploaded from cosmic into ensembl databases , and this has allowed the incorporation of cosmic data directly into the ensembl web pages , as 
these pages display the cosmic mutation in the local sequence context , with annotations on all ensembl transcripts for the gene .
also included are links to ensembl s genomeview websystem , providing views of the mutated gene with full genome annotations .
links back to cosmic have been carefully incorporated into the ensembl website to give more detailed and specialist views of the data .
initially released in august 2010 , the full cosmic data set is expected shortly after .
a number of other external projects have been receiving our support integrating cosmic data , including intogen ( http://www.intogen.org/home ) , uniprot ( http://www.ebi.ac.uk/uniprot ) and pfam ( http://pfam.sanger.ac.uk ) .
many more have used exports from the ftp site to extend existing systems ( e.g. cgwb ; https://cgwb.nci.nih.gov ) , or develop new ones , for example , as integration resources of selected data subsets ( e.g. canprovar ; http://bioinfo.vanderbilt.edu/canprovar ) .
further external projects have integrated cosmic s search feature into their systems , interpreting results of remote search queries for local examination , with links back into the cosmic website ( e.g. onix ; http://www.ncri-onix.org.uk ) .
a stable identifier system has been developed for cosmic somatic mutations to allow external databases to easily link back to the appropriate cosmic record .
cosm i d ( cosmic somatic mutation identifier ) which will remain stable between releases of cosmic .
ensembl is the first external database to successfully use the cosm i d and we ask other database to maintain this identifier when using cosmic annotated mutations .
the data in cosmic are continually updated , to maintain the existing curated genes and to include new fully curated genes  this work will continue . increasing numbers of genes are also being added during the curation of large - scale candidate gene screens which can encompass more than 20  000 genes in one study .
more significantly , there are increasingly numerous studies detailing the full resequencing of entire cancer genomes ; while the first few have already been released in cosmic , it is expected that this will prove a major focus for cosmic s development .
while genome data have already been exported from cosmic into the icgc ( www.icgc.org ) , it is intended that cosmic should also import icgc - validated somatic mutation data to aggregate with genomes curated from elsewhere , maximizing the cancer genome coverage of the cosmic database . in order to effectively interrogate this increasingly huge amount of information ,
gbrowse ( 13 ) is a fully featured and very flexible genome browser , and , to work within cosmic , it has been populated with full genome annotations alongside which cosmic data are easily navigable in a genomic context .
it combines into one window most of the data currently available in cosmic , including all gene structures and sequences , all point mutations , structural rearrangements and copy number aberrations .
in addition to improving the genomic context of cosmic , a new analytical suite is being built for the main gene - centric system also . in similar ways to the existing mutation - type pie charts ( figure 3 ) , new charts and tables are being designed to display mutation information according to constraints such as basepair sequence change or insertion / deletion size .
these will be especially powerful , as they will employ all the specialization filters that are used in deeply examining the gene histogram page as described earlier .
the cosmic project has been running for over 9 years , and is supported to continue for many more . a stable and comprehensive resource
, it is now meeting the challenge of annotating and integrating a wide range of somatic mutation data from many new sources , continuing to make it easily and freely available to the research community .
the wellcome trust supported this work under grant reference 077012/z/05/z . funding for open access charge : wellcome trust .
 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 . 
INTRODUCTION
DATABASE CONTENT
DATA ACCESS
Data integration and interoperability
FUTURE WORK
FUNDING