cosmic

COSMIC v27 released

This months release of COSMIC comprises upgrades to both the web site (which now allows searching by gene/sample name or keyword) and data, with new CGP resequencing studies and curated genes. COSMIC now contains data on over 200,000 tumour samples and 400,000 individual experiments. Of these 202109 tumours, 40331 were found to contain one or more mutations (19.9%).

CGP Resequencing Studies

Two new studies examine our pilot data set comprising 40 cancer cell lines that have a matched normal cell line, allowing all of the mutations to be confirmed as somatic.

Notch signalling proteins

This group of proteins comprise the Notch receptors and other proteins which are involved in Notch signalling. The Notch signalling pathway allows cells to communicate with each other and plays a crucial role in developmental regulation. NOTCH1 mutations have been associated with T-cell acute lymphoblastic leukaemia.

Phosphatidylinositol metabolism

This gene set includes proteins which control the synthesis and turnover of phosphatidylinositol which is synthesised in the endoplasmic reticulum before translocating to cytosolic membrane surfaces where it plays an important role in many cellular processes including cell signalling. Mutations in the phosphatidylinositol-3-kinase PIK3CA and the lipid phosphatase PTEN are associated with many types of cancer.

Literature Curation

STK11 (LKB1)

STK11 is a tumour suppressor, physically associating with p53 to effect growth suppression via p53-dependent apoptosis pathways; restoring gene activity into cancer cell lines defective for its expression results in a G1 cell cycle arrest. It has been identified as the cause of Peutz-Jeghers syndrome, an autosomal dominant disorder inducing an increased risk of melanocytic macules, gastrointestinal polyps and various neoplasms.

STK11 Statistics

Samples	2344
Mutations	92
Unique Sequence Changes	63

WT1

Wilms tumour is a solid cancer usually occurring in childhood, caused by malignant transformation of renal stem cells retaining embryonic differentiation potential. Several tumour suppressor genes have been associated with the development of WT, most classically the WT1 zinc finger DNA binding protein located at chromosome 11p13. A number of isoforms of the transcription factor WT1 exist, unusually exerting control over expression of target genes during both their transcription and splicing.

WT1 Statistics

Samples	1710
Mutations	106
Unique Sequence Changes	68

Website Upgrades

Search Facility

A major update to the COSMIC website this month is the Exalead search facility, allowing for easier navigation of the site. In the 'Text Search' field on the home page, you can search for a gene name or accession number, a sample name or id, or a tumour primary site or sub-site. There is a help page for more advanced searches, which can be accessed by clicking on the question mark in the search box, or the help button in the sidebar.

General Statistics for this release

Experiments	408164
Tumours	202109
Mutant Samples	40331
Mutations	42057
Unique Mutations	7736
Papers curated	4348
Genes	1638

COSMIC third anniversary release (v26)

This release comprises a significant increase in the number of CGP resequencing studies. The five new studies all examine our pilot sample set comprising 40 cancer cell lines that all have a matched normal cell line, allowing all of the mutations to be confirmed as somatic.

Nuclear receptors and cofactors

A related but diverse array of transcription factors interacting with a wide range of coregulatory proteins to form a complex network of multicomponent assemblies serving as coactivators or corepressors of transcription.

SCF and APC cell cycle control complex components

Skp1-cullin-F-box-protein complex (SCF) and the anaphase-promoting complex/cyclosome (APC) are ubiquitination complexes regulating progression through the cell cycle.

Nucleocytoplasmic transport components

Factors involved in both import and export of proteins from the nucleus, including nuclear pore components.

Human homologues of putative target "cancer" genes from transposon screens in the mouse

Human orthologues of genes targeted by insertions in transposon insertion screens for cancer genes in the mouse.

Protein Tyrosine Phosphatases (PTP)

Critical regulators of signal transduction, effecting the reversible phosphorylation of tyrosine residues in cell signalling proteins.

Curated Gene Update

The following fully curated genes also received minor updates : BRAF, CDKN2A, EGFR, ERBB2, FLT3, KIT, KRAS, PDGFRA, PTEN, PTPN11.

General Statistics for this release

Experiments	394675
Tumours	194928
Mutant Samples	39520
Mutations	41228
Unique Mutations	7505
Papers curated	4180
Genes	1516

COSMIC v25 released

This month's COSMIC release comprises significant updates to CGP resequencing studies and curation of the scientific literature.

Update to CGP Resequencing Studies

The six non-kinase CGP resequencing studies have received substantial updates to the number of genes included and the number of mutations found (the kinase studies were updated in November 2006). Fifty two new genes have been added to the DNA repair study, together with three in the Apoptosis and two in the GAP-GEF studies. The number of mutations discovered in each of the six studies has increased as shown below:

Study	Mutation Count
Study	v24	v25
Inositol Polyphosphate Phosphatases	8	12
Heterotrimeric G-Proteins	5	6
DNA repair genes	114	194
Apoptosis genes	38	82
Small monomeric GTPases	8	28
GAP-GEF genes	48	91

Literature Curation

In addition to the CGP resequencing studies, significant updates have been made to those genes which have received complete scientific literature curation. Three genes have been extensively updated, BRAF (19.1%, increased to 19224 samples), JAK2 (25.1%, increased to 11190 samples) and NOTCH1(75.4%, increased to 488 samples), whilst eighteen other genes have received minor updates (less than 10% increase in sample number): ABL1, APC, CDKN2A, CEBPA, CTNNB1, EGFR, ERBB2, FLT3, KRAS, MET, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RET, SRC, VHL.

General Statistics for this release

Experiments	387254
Tumours	193513
Mutant Samples	39003
Mutations	40672
Unique Mutations	7272
Papers curated	4082
Genes	1398

COSMIC v24 released

This months release of Cosmic includes the curation of NPM1 and CDH1.

Curation details for NMP1

NPM1 (Nucleophosmin), is a nucleocytoplasmic shuttling protein and critical regulator of TP53. Frequent mutations have been found in both childhood and adult AML. 20 papers have been manually curated for this gene resulting in the addition of 45 unique mutations (exon 12).

NPM1 statistics

Samples	3870
Experiments	3875
Mutants	1171
Papers	20
Unique Mutations	45

Curation details for CDH1

CDH1 (E-cadherin), is a calcium ion-dependent cell adhesion molecule with loss of function of this gene implicated in cancer invasion and metastasis. In particular, somatic mutations of this gene have been reported in gastric and lobular breast cancer. 181 mutations have been added to Cosmic for this gene from the curation of 46 papers.

CDH1 statistics

Samples	1958
Experiments	1970
Mutants	205
Papers	46
Unique Mutations	181

General Statistics for this release

Experiments	380741
Tumours	190358
Mutant Samples	38206
Mutations	39839
Unique Mutations	7032
Papers curated	4023
Genes	1343

COSMIC v23 released

This months release of Cosmic includes a major update to the protein kinase screens.

Protein Kinase Somatic Data Information

The Cancer Genome Project is pleased to release the full set of protein kinase somatic mutation data resulting from the screening of over 200 human cancers through the full set of 518 annotated genes. Over 1000 mutations have been identified in a combined total of 247 megabases sequenced. This dataset is intended to serve as a catalyst for further biological investigation of mutated kinases and pathways, hopefully leading to new insights and therapeutic opportunities in human cancer.

http://www.sanger.ac.uk/genetics/CGP/Studies/Kinases/

Copy number data update

Oligo array CGH data (using the Affymetrix 10K SNP array) for a further 233 cancer cell lines and 70 primary tumours has been made available increasing the total available from 834 to 1136 samples.

General Statistics for this release

Experiments	374169
Tumours	184092
Mutant Samples	36252
Mutations	37857
Unique Mutations	6758
Papers curated	3945
Genes	1342

COSMIC v22 released

This months release of Cosmic includes the curation from the scientific literature of the APC oncogene and information on the similarity between cell lines is now recorded and displayed in Cosmic.

Curation of APC literature

Mutations in the APC gene are one of the initiating events in colorectal tumorigenesis, both familial and sporadic. Our curation confirms that the majority of mutations occur in the central portion of the gene (the mutation cluster region, 'MCR') where mutations are associated with the most severe phenotype of huge numbers of polyps at a young age, often with extracolonic manifestations. Mutations outside the MCR cause a much milder and late onset phenotype, generating few polyps. We curated 206 papers for APC, finding 1420 mutated samples out of 7115 (almost 20%). As expected, there were no major hotspots; the most frequent mutation was p.R1450*, found in 87 samples (6%).

Web site

On the web site, we have begun to include information in Cosmic on samples found to be significantly similar by their genotype as assessed using Affymetrix SNP arrays. To date, 241 cell lines have been found to have genotypes which are greater than 80% identical with at least one other. This data is now displayed in the Cosmic Sample page under the heading of "Other Cancer Samples from the Same Individual"; here is an example: http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=sample&id=687448

General Statistics for this release

Experiments	290332
Tumours	173929
Mutant Samples	32891
Mutations	34390
Papers curated	3781
Genes	1342

COSMIC v21 released

This months release of Cosmic includes major updates to the Cancer Cell Line Project and microsatellite instability status data sets. In addition, published somatic mutation data from two additional genes, MPL and FGFR1, have been added to Cosmic.

Cancer Cell Line Project Major Update

The Cancer Cell Line Project aims to systematically screen a large panel of cancer cell lines for mutations in known cancer genes, thus empowering these cell lines as biological reagents for further work in anti-cancer agent development and further work on cancer molecular and cellular biology.

For this release of Cosmic, a further 137 cell lines have been added to the working set and 78 duplicate cell lines have been removed. This brings the total number of samples to 787. A further 98 mutations have also been added (See: http://www.sanger.ac.uk/genetics/CGP/CellLines/).

Statistics for the CGP Cancer Cell Line Project

Experiments	12887
Samples	787
Mutant samples	1087
Mutations	1144
Unique Mutations	3519
Genes	21

MSI Data Update

The microsatellite instability (MSI) status for CGP samples under study has been updated, bringing the total number of samples with MSI status to 1,530. (See:-http://www.sanger.ac.uk/genetics/CGP/MSI/msi_page.shtml).

Curation of MPL and FGFR1

Somatic mutations reported in the published scientific literature for the FGFR1 and MPL genes has now been added to Cosmic.
MPL- http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=MPL
FGFR1- http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=FGFR1

General Statistics for this release

Experiments	278786
Tumours	164905
Mutant samples	30566
Mutations	31933
Papers Curated	3611
Genes	1339

COSMIC v20 released

This months release includes NCI-60 updates and mutation data from the scientific literature for VHL.

NCI-60 update

The CGP is pleased to release mutation data for 24 known cancer genes on the NCI-60 series of cancer cell lines. These data should allow for greater power in interpretation of biological data using the lines as well as providing a genetic framework for evaluating response to the large series of compounds screened against this reference cell line set.

Microsatellite instability

Microsatellite instability occurs due to a defect in mismatch repair. This is usually a result of inactivation of MSH2, MLH1 or MSH6 due to a mutation or to reduced expression associated with promoter methylation. Analysis of microsatellite instability was carried out using the BAT markers as described by Rodriguez-Bigas et al. All samples were screened using the markers BAT25, BAT26, D5S346, D2S123 and D17S250. Details of this, when available, are posted on the sample overview page. An example of which can be seen at http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=sample&id=905950

Curation of VHL

VHL mutation data from the literature is now available. We have curated 93 papers covering 3412 experiments. These experiments used 3386 samples, in which 879 mutations were recorded.

General Statistics for this release

Experiments	270623
Tumours	160594
Mutant samples	29154
Mutations	30439
Papers curated	3519
Genes	1338

COSMIC v19 released

This month's release of COSMIC includes the Cancer Genome Project screen of the GAP-GEF gene set and new information displays.

GAP-GEF Screen

This gene set, consisting of 173 genes, is comprised of proteins that function to regulate the activity of proteins with GTPase activities. GTPase activating proteins (GAPs) promote hydrolysis of GTP-GDP. Guanine nucleotide exchange factors (GEFs) promote GDP/GTP exchange. Both classes modulate the function of the small monomeric GTPases (including the RAS oncogene family) and other key signalling proteins that use the conversion of GTP-GDP as a molecular switch to regulate function. This system of GTPase/GAP/GEFs regulates a wide variety of cellular processes including growth, differentiation, survival and motility.

Web Improvements

Zygosity and somatic/germline status information are now available for mutations in COSMIC, CGP Resequencing and Cancer Cell Project websites. The somatic/germline status is listed on the sample detail page and the export function with the following statuses:-

Not specified
Confirmed somatic mutant
Reported elsewhere as a somatic variant
Confirmed germline variant
Reported elsewhere as a germline variant
Variant of unknown origin

Zygosity information is available on the mutation detail page with the following statuses:-

Unknown
Homozygous
Heterozygous

General Statistics for this release

Experiments	264296
Tumours	155902
Mutant samples	27732
Mutations	28859
Papers curated	3419
Genes	1337

COSMIC v18 released

The CGP Resequencing Studies Website is released this month, which will act as a repository for data from CGP resequencing efforts to identify novel somatic mutations in human cancer. The pages have their own distinctive red colour scheme to denote this. Prior data on sets of genes/samples systematically screened for mutations were previously integrated into the "blue" COSMIC pages. This will continue with data now being submitted, prepublication, to and held on the new site. This will allow users to browse, search and evaluate these data more effectively. The web resources that are now available are detailed below:-

COSMIC (Blue): All data screened from literature and CGP based projects.
CGP Resequencing Studies (Red): Somatic mutations from systematic large scale resequencing of genes in human cancers.
CGP Cancer Cell Line Project (Green): Resequencing of known cancer genes and other analyses of human cancer cell lines.

Curation of PTCH

37 papers from the scientific literature have been curated for the PTCH gene in this release. Adding an additional 897 experiments and 168 mutations.

General Statistics for this release (COSMIC)

Experiments	254544
Tumours	153528
Mutant samples	27426
Mutations	28534
Papers curated	3393
Genes	1176

COSMIC DAS track

Ensembl has recently moved to the NCBI 36 assembly of the human genome whilst COSMIC genes and mutations are currently mapped to build 35. This has caused some disparity with the COSMIC DAS track. Therefore we suggest only using the cosmic DAS track on the most recent ensembl archive site(http://feb2006.archive.ensembl.org/index.html).Provided below is a link that will open the appropriate website with the DAS source attached:

http://feb2006.archive.ensembl.org/Homo_sapiens/contigview?conf_script=contigview;c=7:139949999.5:1;w=200000;h=7;add_das_source=(name=COSMIC+url=http://das.ensembl.org/das+dsn=cosmic_ncbi_35+type=ensembl_location+color=blue+strand=b+labelflag=n+stylesheet=y+group=n+depth=0+score=n+active=1)

Cosmic v17 release

This month's release of COSMIC includes the Cancer Genome Project screen of small monomeric GTPases and mutation data from the scientific literature for MADH4.

CGP Small Monomeric GTPase Screen

The small monomeric GTPases function as key molecular switches impacting a large variety of cellular functions such as motility, cell signalling, transcription and the binding, hydrolysis and exchange of GTP/GDP. The RAS subfamily (HRAS, NRAS, KRAS) of small monomeric GTPases were amongst the first identified human oncogenes and are mutationally activated in a wide variety of human cancers.

Curation of MADH4

70 papers from the scientific literature have been curated for the MADH4 gene in this release. Adding an additional 2275 experiments and 259 mutations.

Gene Updates

Further data from the scientific literature for 9 genes, including KRAS and NRAS, has been added for this release. A detailed breakdown for each gene can be seen below.

Gene Name	Additional experiments	Additional mutations
CDKN2A	668	71
CTNNB1	140	8
EGFR	150	4
ERBB2	84	1
HRAS	54	1
KRAS	3050	647
NRAS	1611	203
PTEN	37	7
PTPN11	309	17

General Statistics for this release

Experiments	249331
Tumours	149251
Mutant samples	26574
Mutations	27637
Papers curated	3324
Genes	1175

COSMIC v16 released

Released for March are data from a kinase domain screen of malignant gliomas. These data cover approximately 400kb of sequence in each of 9 tumours, including data from recurrent/resistant tumours.

We have recently completed a screen for somatic mutations of the kinase domain encoding exons of the entire protein kinase family in a series of human malignant gliomas. The results are presented in this release of COSMIC. No commonly mutated kinase domain was found in these studies. However, as is the case with our other work in this area, deep sequencing data from human tumours is informative about the processes that have contributed to oncogenesis in the patient. Two gliomas recurrent after temozolomide (alkylator) chemotherapy, but not a third recurrent after XRT alone, had the highest mutation prevalence of any tumours we have analysed to date. These data suggests a link between mutation prevalence and recurrent/resistant brain tumours treated with alkylator chemotherapy.

Statistics

Experiments	235213
Tumours	143427
Mutant samples	25360
Mutations	26388
Papers curated	3207
Genes	1035

A COSMIC Expansion

The Catalogue Of Somatic Mutations In Cancer is two years old and has mutation data for over 1,000 genes, curated from over 3,000 published papers and unpublished data from the Cancer Genome Project.

The original aim of COSMIC continues with the curation of somatic mutation information from the literature for known cancer genes. During 2005 data for 9 genes was collected; ABL1, CDKN2A, EGFR, GATA1, JAK2, MSH6, NOTCH1, PTPN11 and SMO. In addition to this, genes that were curated in 2004 were updated as new data was published.

The number of genes in COSMIC expanded rapidly when the Cancer Genome Project at the Wellcome Trust Sanger Institute published 3 studies of somatic mutations in the protein kinase gene family (518 genes in total). This data provides a unique insight to the somatic mutations in breast, lung and testicular cancers.

More recently the Cancer Genome Project has been submitting unpublished somatic mutation data to COSMIC (link). The data comes from genes involved in apoptosis, DNA repair, maintenance and metabolism and the Inositol Polyphosphate Phosphatase and Heterotrimeric G-Protein families.

In another new departure the COSMIC software was used to create a new web site the Cancer Cell Line Project. This separate site, with it's own 'mint' colour scheme, contains the results from the sequence analysis of 14 known cancer genes in over 700 cancer cell lines. Initial sequence data for 4 genes analysed in the NCI-60 is also available. This work is in progress and more results will be posted in the coming months. What is more, the number of genes in this project will continue to increase; providing genetic data for this wide set of cancer cell lines.

There have been many enhancements to the web site over the past 12 months. A tissue overview provides a summary of mutations reported in a selected tissue. New pages were created to show more details of mutations and samples and give greater depth to the data. There are also links to other data such as genome copy number information.

COSMIC has been summarised in The British Journal of Cancer (Forbes et al, 2006).

This month sees the update of; BRAF, CDKN2A, EGFR, ERBB2, HRAS, KRAS, NRAS, PTEN, PTPN11 and SMARCB1. In addition the Cancer Genome Project has submitted unpublished data for genes involved in apoptosis.

There are plans to continue the development of COSMIC in terms of data content and data presentation. We are always happy to receive feedback and suggestions (email: cosmic@sanger.ac.uk).

Statistics

Experiments	228,669
Tumours	142,569
Mutant samples	25,176
Mutations	26,194
Papers curated	3,013
Genes	1,035

COSMIC v14 released

The COSMIC team is proud to announce the release of COSMIC-14 with data for CDKN2A(p16) and more unpublished data from the CGP.

DNA REPAIR, MAINTENANCE AND METABOLISM

The Cancer Genome Project has released further unpublished somatic mutation data from a screen of 41 cancer cell lines. The 302 genes in this release are involved or associated with DNA repair, maintenance and metabolism. The genes can be viewed together or in 5 subgroups; Telomerase Complex, SWI/SNF, DNA replication, Nucleotide Metabolism and DNA Damage Response and Repair. In total 119 somatic mutations were identified in this study.

CURATION OF CDKN2A

CDKN2A (also known as p16) is a tumour suppressor. It induces cell cycle arrest by inhibiting the phosphorylation of Rb by the cyclin-dependent kinases CDK4 and CDK6. So far 453 papers have been curated for this gene with 2,591 mutations recorded from 16,883 samples.

STATISTICS

Experiments	219,037
Tumours	140,212
Mutant samples	24,817
Mutations	2,637
Papers curated	3,379
Genes	870

COSMIC v13 released

Somatic mutation data from new gene families

In a major new departure the Cancer Genome Project is proud to release further somatic mutation data. The results from the sequencing of two gene families, Inositol Polyphosphate Phosphatases and Heterotrimeric G-Proteins, have been added to the data for the Protein Kinase genes . This data will be expanded in the future with the addition of further gene sets.

Updates to existing genes

Nine genes in COSMIC have been updated with further data; NRAS, RB1, ERBB2, HRAS, PTEN, TP53, KRAS, APC and CDKN2A

New DAS data source

The Cancer Genome Project is pleased to announce the release of a DAS source devoted to the genes and mutations within COSMIC. Using this source you will be able to view the genes and mutations from COSMIC within a genome browser or the DAS client of your choice.

All 587 genes in COSMIC are exported as features. Each of these features displays the genomic 'footprint', which encompasses both exonic and intronic sequence between the start and end points of the CDS sequence. A link is attached to each feature, providing a mechanism for the client to link back directly to the gene entry on the COSMIC website.

In addition to the gene footprints, there are also a large number of unique mutations. These are also displayed as features, with links back to the mutation summary page in COSMIC. The database currently holds 2812 unique mutations, of which 1035 are currently exported. This subset is comprised of all the single nucleotide substitutions. More complex mutations will be included, as the genomic coordinates are mapped.

The DAS source can be found at the following URI:

http://das.ensembl.org/das/cosmic_genomic

The easiest way to view this source is to place the following URI in your browser:

http://www.sanger.ac.uk/turl/6d8

This will attach the DAS source and display some of the mutations found in BRAF. Additional configuration can be performed on the track, by clicking on the track name. For more information, see the help pages on the Ensembl website.

COSMIC statistics

Experiments	190,576
Tumours	124,381
Mutant samples	23,232
Mutations	2,228
Papers curated	2,812
Genes	587

COSMIC version 12 released

The November release of COSMIC has further data on 9 known cancer genes.

GENE UPDATES

The genes with additional data are; BRAF, PTEN, RB1, EGFR, TP53, CDKN2A, NRAS, KRAS and PIK3CA.

VERSION

We have implemented a versioning system for the data in COSMIC. The current release is version 12 with a plan to release a new version every month.

CANCER CELL LINE PROJECT.

There are additional mutations for the known cancer genes being sequenced through the cancer cell lines. Notably there is data for homozygous deletions in the CDKN2A gene.

COPY NUMBER DATA

The Cancer Genome Project has released more copy number data derived from the analysis of cancer cell lines and primary tumours using Affymetrix SNP microarrays. So far a total of 834 samples have been analysed consisting of 161 primary tumours and 673 cancer cell lines. This data is freely available from the CGP website. The primary tumours overlap with those being sequenced by the CGP while the cancer cell lines include those being sequenced in the Cancer Cell Line Project.

COSMIC STATISTICS

Tumours 124,367

Experiments 188,529

Mutations 23,157

Papers 2,224

Genes 538

COSMIC Update

COSMIC has been updated with the addition of 2 new curated genes and new mutation descriptions.

MUTATION DESCRIPTIONS

COSMIC has adopted the Human Genome Variation Society sequence variation/mutation nomenclature for the bulk of the mutations in COSMIC. This represents a major upgrade with the aim of improving clarity and enables the listing of intronic variants for the first time.

GENE UPDATES

Two genes have further data in COMSIC; EGFR and PTEN.

PROTEIN KINASE MUTATIONS IN TESTICULAR CANCER

The sequence analysis of the protein kinase gene family in human testicular germ-cell tumours of adolescents and adults has been published. The mutation data from this work was previously available in COSMIC and is now joined by the published analysis of the data.

CANCER CELL LINE PROJECT

There are additional mutations from the screening of known cancer genes through an extensive set of cancer cell lines.

STATISTICS FOR COSMIC

Tumours	123,197
Experiments	186,181
Mutations	22,711
Papers	2,157
Genes	537

COSMIC Update

COSMIC has been updated with the addition of 3 new curated genes; MSH6, NOTCH1 and PTPN11.

There is a new member to the COSMIC family; the Cancer Cell Line Project. This portal uses the COSMIC code to serve mutation data from the cancer cell lines being sequenced by the Cancer Genome Project at the Wellcome Trust Sanger Institute. The cell line data is presented in the same style as the COSMIC data with a unique colour scheme. There are links to jump from the Cancer Cell Line Project pages to view all of the data in COSMIC. At present there is data from 12 known cancer genes in the Cancer Cell Line Project database.

In addition the results from the screen of all 518 protein kinase genes in lung cancer, that were available in the previous release of COSMIC, have been published in Cancer Research

NEW GENES IN COSMIC

MSH6 - is a member of the MutS homolog family and is required for DNA mismatch specific binding. Almost one third of tumours of the large intestine have somatic mutations in this gene.
NOTCH1 - has somatic small intragenic mutations in 60% of haematopoietic and lymphoid tumours.
PTPN11 - is a nontransmembrane protein-tyrosine phosphatase. Approximately 6% of haematopoietic and lymphoid tumours have mutations in this gene.

COSMIC STATISTICS

Experiments	186014
Tumours	123039
Mutations	22598
References	2153
Genes	537

Protein kinase mutations in lung cancer

The Cancer Genome Project has sequenced all protein kinase genes in lung cancer - the most common cause of cancer deaths worldwide

There are over 27,000 new cases of lung cancer in the United Kingdom each year. Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. The Cancer Genome Project has screened the complete coding sequence of all 518 protein kinase genes in 33 lung cancers. This study, published in Cancer Research, is the largest survey reported to date of somatic mutations in lung cancer.

The Cancer Genome Project at the Wellcome Trust Sanger Institute was established in 2000. Its goal is to identify mutations that occur in cancer cells to enable the development of new diagnostics and new treatments and advance our understanding of the biology of cancer.

The Wellcome Trust Sanger Institute Cancer Genome Project and their collaborators have published the latest results of their survey of genes that might be implicated in cancer. The report is published in Cancer Research on Thursday 1st September 2005 and is also available through COSMIC.

The gene set chosen was a class called protein kinases, key controllers of cell growth and death. Members of this family have been shown to be important in cancer. However, the whole set has never been sequenced in a single set of lung tumours. The study generated over 40 million bases of DNA sequence (1.3 million for each sample).

This work identified 188 somatic mutations in 141 protein kinase genes. There was considerable variation in the number of mutations found in each tumour. The results indicate that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent. Larger studies are warranted to further explore these initial findings. Cancer is a complex set of diseases that will affect 1 in 3 people. This work in the CGP is but one part of a global effort to further understanding of cancer and move towards better diagnosis and treatment.

COSMIC Website Update

The COSMIC web site has been updated with additional data from the literature and unpublished data from the Cancer Genome Project.

SOMATIC MUTATION DATA FOR KNOWN CANCER GENES

Data for 3 genes has been curated from the literature and included in COSMIC; ABL1, GATA1 and SMO.

SOMATIC MUTATIONS OF THE PROTEIN KINASE GENE FAMILY

The screen of the protein kinase gene family by the Cancer Genome Project now includes two new tumour types; lung cancer and testicular germ-cell tumours. There are marked differences in the mutation prevalence between these two tumour types.

CANCER CELL LINE PROJECT

The mutation data for 9 further genes has been included on the web site giving a total of 550 mutations. The genes are APC, CDH1, CTNNB1, HRAS, MADH4, PIK3CA, PTEN, RB1 and STK11. The sequencing of these genes is not necessarily complete but the cell lines with mutations have been confirmed and the experiments will continue to finish this work.

COSMIC STATISTICS

179,563 Experiments

118,134 Tumours

22,005 Mutations

2,090 References

534 Genes

Cosmic Update

COSMIC now includes data from a screen of all protein kinase genes in breast cancer and an update of mutation data from the literature.

New Data

The data in COSMIC has expanded to include a new data type and the number of known cancer genes has been extended with updates on some of the existing cancer genes.

A screen of the coding sequence of the protein kinase genes in breast cancer.

The Wellcome Trust Sanger Institute Cancer Genome Project and their collaborators have published the latest results of their survey of genes and their mutations in cancer. The report was published online in Nature Genetics on Sunday 22 May 2005 (more). This data has been integrated with the existing data in COSMIC and made available through the web site.

New cancer genes in COSMIC

The mutation data for two further cancer genes has been curated from the scientific literature and added to COSMIC.

EGFR - mutations in the epidermal growth factor receptor (EGFR) have been reported in lung cancer and have been associated with the tumour response of patients receiving gefitinib.

JAK2 - A single somatic point mutation (V617F) has been identified in JAK2 in patients with polycythaemia vera. The mutation alters a highly conserved valine present in the negative regulatory JH2 domain, and is predicted to dysregulate kinase activity.

Updates to existing COSMIC genes

Further published data has been curated for 5 genes in COSMIC; BRAF, ERBB2, FGFR2, PDGFRA and PIK3CA.

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We have created a new mailing list: COSMIC-announce, with a subscription link located at the bottom of the home page. As a subscriber to this list you will recieve announcements about the latest COSMIC news and website releases.

Browsing by Gene

More improvements have been made to the gene selection pages. The alphabetical lists have been seperated into 3 groups to reduce the amount of guess work involved in finding your gene of interest.

Genes from the Cancer Gene Census: - This list contains genes that have been included in the Cancer Gene Census. All of the genes in previous releases of COSMIC are included in this census.

Other Genes with Mutations: - These genes are not in the census, but have been found during the curation of the literature and so are included in the database. All these genes have a documented mutation which is thought to be linked to cancer.

Other Genes without Mutations: - The final list contains all the other genes that have been recorded during curation. These do not have a documented mutation in the references found in COSMIC.

The karyotype has also been updated. Genes from the census can be located quickly by clicking on the red trinagles. All other genes are indicated by blue lines across the chromosome.

Mutation Overview Page

Each mutation in COSMIC now has its own overview page containing information about the type of mutation and samples/tissues containing the mutation. This page can be reached by clicking on various links throughout the website.

Main Histogram:

Main Mutation table:

Sample Overview Page:

The overview page is divided into 8 main sections:

Mutation Id: This id is used to identify a mutation within the COSMIC database and is assigned as the mutation is curated.

Mutation type: The mutation type is used to describe the type of mutation that has occurred. This can be anything from a single base inframe substitution, to a frameshift deletion.

Mutation Location: Here, an image displays the location of the mutation within the peptide sequence.
- The grey bar at the top of this section shows the full length sequence. Below this can be found a red box, which indicates the area around the mutation. At the bottom of the image, the red box has been expanded and the peptide sequence around the mutation is shown. Here you will find a red triangle which indicates the starting point of the mutation. Clicking on the triangle will produce a pop-up window showing the mutation at both the peptide and nucleotide level.
- Additionally there is a link, 'Show all mutations in area', to the main histogram page for the gene. This link will show the gene histogram zoomed into the area displayed on this page. This allows you to see any other mutations that have been identified in the surrounding area.

Gene: The name of the gene in which the mutation was found. Clicking on the gene name will link to the summary page for that gene.

AA Mutation: This section details the change that has occurred in the peptide sequence as a result of the mutation. Formatting is as follows:
- Substitutions - X(Y)Z
  Where X is the amino acid found in the wildtype sequence. Y is a number representing the position, within the peptide sequence, at which the mutation occurred. Finally, Z is the amino acid found in the mutant sequence.
- Deletions - delY(Z)
  Where Y is a number representing the position at which the deletion starts and Z is the amino acid sequence which has been deleted.
- Insertions - insY(Z)
  Where Y is a number representing the position at which the insertion begins and Z is the amino acid sequence that is inserted.

CDS Mutation: This section details the change that has occurred in the nucleotide sequence as a result of the mutation. Formatting is identical to the method used for the peptide sequence.

Tissue Distribution (Top 5): The top five tissues in which this mutation has been identified are described in the following bar chart.
- Each bar represents the number of samples, for a specific tissue type, that have exhibited the selected mutation. A label indicating the name of the tissue type and the number of samples is located below each bar.
- Clicking on one of the bars will take you to the tissue overview page for the selected tissue.

Associated Samples: A list showing all the samples, including their primary tissue types, that have the selected mutation. Clicking on a sample name will take you to the sample summary page for the selected sample. Clicking on the primary tissue type will take you to the tissue overview page.

Sample Overview

Two new sections have been added to this page:

Tumour Features: In this section details about the tumour, from which the sample was obtained, are listed whenever they have been supplied by the reference source.

External Data Sources: Additional data sources, with information about the sample, are listed here when available. This includes information from some of the studies within the Cancer Genome Project.

References

COSMIC now includes review papers. There is a review section that can be found at the bottom of the reference overview page for each gene. This section includes references that review other works. As the data from these references has already been added to the data from the original sources, this data is not added again.

Statistics

529 Genes

114300 Tumours

20536 Mutations

1894 References

COSMIC Website Update

COSMIC presents 'Tissue Overview' another way to view somatic mutation data. The Tissue Overview page details the Top 5 Genes for any tissue / histology selection ranked by mutation frequency and data volume. In addition it lists other genes with and without mutations for the selection. From the Tissue Overview page you can click through to the specific details of the listed genes.

Website

Home Page

We have updated the entry point system.

Detailed Search - This has been the standard search pathway and has not changed from previous releases. Please continue to use this pathway to build complex queries, if you are interested in specific subtissues or histologies
Quick Search - This is a new pathway greatly reducing the number of steps required to access the tissue overview page and any subsequent pages. This increase in speed does however reduce the complexity of the available search to just primary tissues.

Tissue Overview

As stated above, this new page details all the genes that have samples for the tissues / histologies selected. It is split into three major sections, with the first section detailing what we feel are the most important genes, based on mutation frequency and data volume.

Section One: Top Genes With Sample Data

This section provides an interactive bar chart and table showing data for the highest ranked genes containing samples from the chosen tissues / histologies

The coloured bars in the image represent:

All Samples
Samples With Mutations

Clicking on any portion of the bar or name associated with a particular gene will reveal a pop-up menu.

Sample Number: (count) - This indicates the number of samples that have been found with the selected tissue/histology type
Mutated Samples: (count) - This is the number of the above samples that have shown mutations.
Go to Full Gene Display - Clicking on this link will take you to the histogram display for the selected gene.

Below the bar chart image is a table that displays all the information found in the image, in a tabular format.

Section Two: Other genes with mutations

This section contains a list of additional genes with mutated samples that didn't make it into the top 5. Each gene name is linked to the full histogram image.

Section Three: Other genes without mutations

This section contains a list of additional genes without mutated samples that didn't make it into the top 5. Again, each gene name is linked to the full histogram image.

COSMIC's first anniversary

The COSMIC database and web site have been updated and now have somatic mutation data from 21 genes.

New Data

CEBPA is mutated in 7% of haematopoietic and lymphoid tissue tumours. It arrests cell proliferation by inhibiting the kinases CDK2 and CDK4.
CTNNB1 or beta-catenin is mutated in a variety of tumours. The gene encodes an adherens junction protein that is critical for the establishment and maintenance of epithelial layers
KIT is characterised by two clusters of mutations in and around the kinase domain of the gene with frequent mutations in haematopoietic and lymphoid tissue tumours (19%) and soft tissue tumour (32%).
PTEN has mutations through the whole coding sequence with a hot spot at codon 130. Tumours of the central nervous system and endometrium frequently have mutations in this gene (19% and 34% respectively)
SRC is homologous to the v-src gene of the Rous sarcoma virus and has one mutation that has been found in 10 samples.
SUFU encodes a component of the sonic hedgehog/patched signaling pathway and is mutated in central nervous system tumours.

Statistics

21 genes

104,682 tumours

18,478 samples have mutations

1,755 unique mutations

1,672 papers have been curated

COSMIC Update

The COSMIC team is proud to release somatic mutation data for CSF1R, RB1, RET and SMARCB1. This information has been curated from the scientific literature. Somatic mutation data from 15 genes can be queried and viewed through the COSMIC web site.

Data

The 4 new genes in COSMIC give data on specific tumour types and increase the breadth of information that can be queried and displayed.
CSF1R, also known as the oncogene FMS, is a receptor kinase that is mutated in ~5% of myelodysplastic syndrome cases. Mutations in this gene have been associated with a predisposition to myeloid malignancy.
RB1 is mutated in more than 11% of the tumours that have been studied. It is frequently somatically mutated in cases of retinoblastoma (47%) while germline mutations predispose to the same disease.
RET, a tyrosine kinase receptor, is somatically mutated in 38% of thyroid medullary carcinomas. Germline mutations in the RET gene are associated with multiple endocrine neoplasia, type IIA and type IIB, medullary thyroid carcinoma and Hirschsprung disease.
SMARCB1, also known as SNF5/INI1, is frequently somatically mutated in soft tissue rhabdoid tumours (41%). These are highly malignant cancers that usually occur in young children.

Statistics

15 genes

73,767 tumours

13,420 samples have mutations

536 unique mutations

1,104 papers have been curated

COSMIC Update

The COSMIC team are proud to include somatic mutation data for FGFR2, FGFR3, FLT3, MET, PDGFRA and PIK3CA on the COSMIC web site.

Data

The number of genes with data in COSMIC has more than doubled in this release of the database. The additional data represents a set of genes that have a lower, but nevertheless important, mutation frequency in human cancer as a whole. In specific malignancies genes such as FLT3 do have a significant role as can be seen from the data collected in COSMIC.

Gene	Number of analysed samples	Number of samples with mutations
BRAF	5158	736
ERBB2	714	8
FGFR2	30	2
FGFR3	1735	481
FLT3	7610	1499
HRAS	11876	477
KRAS2	35716	8302
MET	1081	59
NRAS	13884	1132
PDGFRA	146	25
PIK3CA	396	89
TOTAL	78346	12810

Number of unique mutations 307

Number of curated papers 976

Website Changes

Home Page

We have added a link to an ATOM feed for those people with ATOM enabled news feed readers. Adding this link to your feeds list will allow you to see the latest news from the COSMIC site as and when it is available.

Distribution View

A totals column has been added to the 'Details' table to show the total number of mutated samples that are listed.
Links to show only negative data have been added to the'More Details' links in the 'Details' table.
The Insertions and deletions table has been split to show different information for the two types of mutation.

Gene Selection

Genes can now be selected by chromosome, from the karyotype graphic, or as always from an alphabetical list.

References Page

The complete list of references for a specific gene can now be exported in a variety of formats including Excel.

Mutation Data Page

All pages with samples containing more than 100 samples have been split to reduce their size. However, the export function will still export all the samples as selected.

COSMIC Update

We are pleased to announce an update to the COSMIC website. To coincide with the nature paper on ERBB2 we have added all the data for this gene to COSMIC. There have also been a number of improvements to the interface that we hope you will find useful.

New Data

ERBB2

Today, Nature publish our recent findings, the first description of small intragenic ERBB2 mutations in human cancer. Primarily found in non-small cell lung adenocarcinomas, the mutations identified are suggestive of inappropriate activation of ERBB2 kinase activity.

This addition brings 8 new mutations and 714 new samples to the database. Increasing the total number of mutant samples to 10655 and the total number of samples to 58032.

Website Changes

Distribution View

The summary table has been removed in favour of a new gene summary page. Containing all the data from this table, plus much more.
The mutations tables have been expanded to show insertions, deletions and complex mutations.
Information about the negative samples is now available and can be viewed by clicking on the 'More Details' link in the Details table. Like the positive samples, this data can also be exported in various formats.
A new insertions and deletions track has been added to the main image. This will allow us to display a larger number of genes with more complex mutation sets.
A complex mutations track has also been added to display those mutations (multiple base substitutions) which don't quite fit into any of the other categories.

Gene Summary Page

This has grown from the original four row summary table, on the distribution page, into a full page overview of the information stored about a specific gene.

Mutation hot spots: The mutation summary shows those areas of the transcript that have a high density of mutations. This can be used to go directly to the area of interest on the mutation distribution view.
References: A quick glance will show the most recently published paper that was analysed by the COSMIC staff.

Sample Summary Page

Here you will find a page containing all the information about a particular sample. Some of the previously unavailable information, such as details about the individual, has been been made available.

Genes Tested: Quickly identify all the genes in COSMIC that have been tested against the selected sample.
References: Locate all the references that have included the sample.

Reference Summary Page

For the first time in COSMIC you can see all the samples from one paper in one location. In addition to this there are also details about the genes screened and the mutations that were found.

Cosmic Update

We are pleased to announce a minor update to the COSMIC website. The user interface has been updated to include new features that we hope will make your experience with the site more productive and enjoyable.

Web Site Changes

Shorter URLs' - These have been shortened to reduce the amount of text required to link to a specific page within the site. The old style identifiers have been replaced with shortened initials. For example, 'locus_name' has been replaced with 'ln'. The old style links still work and any existing bookmarks should not be affected by this change.
Nucleotide Tracks - All mutations can now be viewed with respect to the changes they would cause to the nucleotide sequence, in addition to the already present amino acid changes. The nucleotide views can be accessed by selecting 'cDNA' in the navigation menu on the main display pages. An example of this view can be seen here
Navigation & Selection Improvements - The selection process has been updated to allow users to select sub types across a range of up to five tissue types. Adding a new level of refinement to the search process.

COSMIC Detailed

The British Journal of Cancer have released an advance online version of an article describing COSMIC. Detailed information is provided about the curation and structure of the database. Followed by a description of the facilities provided by the website.

COSMIC Website Unavailable 8th May

On Saturday 8th May the COSMIC website, as part of the Sanger website, will be unavailable whilst major network upgrades and essential maintenance work is carried out. We apologise in advance for this loss of service.

Nucleotide data available

COSMIC displays mutations at the amino acid level to show the potential implication of the mutations on the protein sequence. In addition to this COSMIC holds the mutations at the nucleotide level. This data is available through the Export function that can be found at the top of the Distribution figure (example ) or at the bottom of the expanded Mutation Data tables (example).

COSMIC version 1 released

Wellcome Trust Sanger Institute launches Catalogue Of Somatic Mutations In Cancer. In the quest to develop rational approaches to treating cancer, researchers need efficient access to existing knowledge. COSMIC (Catalogue Of Somatic Mutations In Cancer), launched today by the Cancer Genome Project at The Wellcome Trust Sanger Institute, is a new tool that provides integrated genetic data from cancer genes, and will make research faster and easier.

BRAF V599E becomes V600E

The original BRAF mutations reported by Davies et al were mapped to the DNA sequence NM_004333[gi;4757867] with the common BRAF mutation being V599E. On the 24th July 2003 this sequence was updated to NM_004333[gi;33188458] with the insertion of 3bp in the coding sequence. The net effect of this update was to increase the length of the BRAF protein by one amino acid and increase the position of all published mutations by one amino acid. The beginning of both versions of the proteins are;



MAALSGGGGGGAEPGQALFNGDMEPEAGAGR PAASSAADP	NM_004333[gi;4757867]
||||||||||||||||||||||||||||||  |||||||||
MAALSGGGGGGAEPGQALFNGDMEPEAGAGAGAAASSAADP	NM_004333[gi;33188458]

The BRAF mutations in COSMIC are mapped to the latest version of the cDNA and V599E has become V600E.