> For the complete documentation index, see [llms.txt](https://help.connected.illumina.com/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://help.connected.illumina.com/annotation/data-sources/cosmic.md). # COSMIC ### Overview COSMIC, the Catalogue of Somatic Mutations in Cancer, is the world's largest source of expert manually curated somatic mutation information relating to human cancers. {% hint style="info" %} **Publication** John G Tate, Sally Bamford, Harry C Jubb, Zbyslaw Sondka, David M Beare, Nidhi Bindal, Harry Boutselakis, Charlotte G Cole, Celestino Creatore, Elisabeth Dawson, Peter Fish, Bhavana Harsha, Charlie Hathaway, Steve C Jupe, Chai Yin Kok, Kate Noble, Laura Ponting, Christopher C Ramshaw, Claire E Rye, Helen E Speedy, Ray Stefancsik, Sam L Thompson, Shicai Wang, Sari Ward, Peter J Campbell, Simon A Forbes. (2019) [COSMIC: the Catalogue Of Somatic Mutations In Cancer](https://academic.oup.com/nar/article/47/D1/D941/5146192), *Nucleic Acids Research*, Volume 47, Issue D1 {% endhint %} {% hint style="warning" %} **Professional data source** This is a Professional data source and is not available freely. Please contact if you would like to obtain it. {% endhint %} ### Small Variants Our main COSMIC deliverable provides annotations for both coding and non-coding variants throughout the genome. As of COSMIC v96, this includes 28.7M variants spanning the human genome. Illumina Connected Annotations currently parses four files to extract the relevant content: * CosmicCodingMuts.vcf.gz * CosmicNonCodingVariants.vcf.gz * CosmicMutantExport.tsv.gz * CosmicNCV.tsv.gz #### VCF extraction **Example** ```scss #CHROM POS ID REF ALT QUAL FILTER INFO 1 65797 COSV58737189 T C . . GENE=OR4F5_ENST00000641515;STRAND=+;LEGACY_ID=COSN23957695;CDS=c.9+224T>C;AA=p.?;HGVSC=ENST00000641515.2:c.9+224T>C;HGVSG=1:g.65797T>C;CNT=1 ``` **Parsing** From the VCF files, we're mainly interested in the following columns: * `CHROM` * `POS` * `ID` * `REF` * `ALT` #### TSV extraction **Example** ```scss Gene name Accession Number Gene CDS length HGNC ID Sample name ID_sample ID_tumour Primary site Site subtype 1 Site subtype 2 Site subtype 3 Primary histology Histology subtype 1 Histology subtype 2 Histology subtype 3 Genome-wide screen GENOMIC_MUTATION_ID LEGACY_MUTATION_ID MUTATION_ID Mutation CDS Mutation AA Mutation Description Mutation zygosity LOH GRCh Mutation genome position Mutation strand Resistance Mutation Mutation somatic status Pubmed_PMID ID_STUDY Sample Type Tumour origin Age HGVSP HGVSC HGVSG MCF2L_ENST00000375604 ENST00000375604.6 3372 14576 RK091_C01 1918867 1806188 liver NS NS NS carcinoma NS NS NS y COSV65049364 COSN1601909 113108365 c.73+3096A>G p.? Unknown het 38 13:113005079-113005079 + - Variant of unknown origin 322 fresh/frozen - NOS primary ENST00000375604.6:c.73+3096A>G 13:g.113005079A>G ``` **Parsing** From the TSV file, we're mainly interested in the following columns: * `GENOMIC_MUTATION_ID` * `ID_sample` * `Primary site` * `Site subtype 1` * `Primary histology` * `Histology subtype 1` * `Pubmed_PMID` * `Resistance Mutation` * `Mutation somatic status` {% hint style="info" %} For all the histologies and sites, we replace all the underlines with spaces. `salivary_gland` would become `salivary gland`. {% endhint %} **Parsing** To aggregate the data in Illumina Connected Annotations, we perform the following: * Parse the coding and non-coding TSV files to retrieve the histologies, sites, PubMed IDs, somatic status, and resistance mutation status. Histologies and sites are tracked with respect to sample IDs. * Parse the coding and non-coding VCF files to retrieve the genomic variant for each entry **Aggregating Histologies & Sites** For sites and histologies, we observe that the subtype provides additional description but is still dependent on the primary site value. For example, the primary site might be `skin`, but the subtype is `foot`. Therefore, we will combine the values in the following manner: `skin (foot)`. COSMIC uses `NS` to show that a value is empty. If the subtype is `NS`, we will use the primary histology instead. #### Download URL **GRCh37** * [CosmicCodingMuts.vcf.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh37/cosmic/v96/VCF/CosmicCodingMuts.vcf.gz) * [CosmicNonCodingVariants.vcf.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh37/cosmic/v96/VCF/CosmicNonCodingVariants.vcf.gz) * [CosmicMutantExport.tsv.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh37/cosmic/v96/CosmicMutantExport.tsv.gz) * [CosmicNCV.tsv.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh37/cosmic/v96/CosmicNCV.tsv.gz) **GRCh38** * [CosmicCodingMuts.vcf.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh38/cosmic/v96/VCF/CosmicCodingMuts.vcf.gz) * [CosmicNonCodingVariants.vcf.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh38/cosmic/v96/VCF/CosmicNonCodingVariants.vcf.gz) * [CosmicMutantExport.tsv.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh38/cosmic/v96/CosmicMutantExport.tsv.gz) * [CosmicNCV.tsv.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh38/cosmic/v96/CosmicNCV.tsv.gz) #### JSON Output ```json { "id":"COSV58272668", "numSamples":8, "refAllele":"-", "altAllele":"CCT", "histologies":[ { "name":"carcinoma (serous carcinoma)", "numSamples":2 }, { "name":"meningioma (fibroblastic)", "numSamples":1 }, { "name":"carcinoma", "numSamples":1 }, { "name":"carcinoma (squamous cell carcinoma)", "numSamples":1 }, { "name":"meningioma (transitional)", "numSamples":1 }, { "name":"carcinoma (adenocarcinoma)", "numSamples":1 }, { "name":"other (neoplasm)", "numSamples":1 } ], "sites":[ { "name":"ovary", "numSamples":2 }, { "name":"meninges", "numSamples":2 }, { "name":"thyroid", "numSamples":2 }, { "name":"cervix", "numSamples":1 }, { "name":"large intestine (colon)", "numSamples":1 } ], "pubMedIds":[ 25738363, 27548314 ], "confirmedSomatic":true, "drugResistance":true, /* not in this particular COSMIC variant */ "isAlleleSpecific":true } ``` | Field | Type | Notes | | ---------------- | :---------: | -------------------------------------------------------------- | | id | string | COSMIC Genomic Mutation ID | | numSamples | int | | | refAllele | string | | | altAllele | string | | | histologies | count array | phenotypic descriptions | | sites | count array | tissue types | | pubMedIds | int array | PubMed IDs | | confirmedSomatic | bool | true when the variant is a confirmed somatic variant | | drugResistance | bool | true when the variant has been associated with drug resistance | **Count** | Field | Type | Notes | | ---------- | :----: | ----------- | | name | string | description | | numSamples | int | | ### Gene Fusions Gene fusions are manually curated from peer reviewed publications by expert COSMIC curators. A comprehensive literature curation is completed for each fusion pair when it is released in the database. Currently COSMIC includes information on fusions involved in solid tumours and leukaemias. #### TSV extraction **Example** ```scss SAMPLE_ID SAMPLE_NAME PRIMARY_SITE SITE_SUBTYPE_1 SITE_SUBTYPE_2 SITE_SUBTYPE_3 PRIMARY_HISTOLOGY HISTOLOGY_SUBTYPE_1 HISTOLOGY_SUBTYPE_2 HISTOLOGY_SUBTYPE_3 FUSION_ID TRANSLOCATION_NAME 5'_CHROMOSOME 5'_STRAND 5'_GENE_ID 5'_GENE_NAME 5'_LAST_OBSERVED_EXON 5'_GENOME_START_FROM 5'_GENOME_START_TO 5'_GENOME_STOP_FROM 5'_GENOME_STOP_TO 3'_CHROMOSOME 3'_STRAND 3'_GENE_ID 3'_GENE_NAME 3'_FIRST_OBSERVED_EXON 3'_GENOME_START_FROM 3'_GENOME_START_TO 3'_GENOME_STOP_FROM 3'_GENOME_STOP_TO FUSION_TYPE PUBMED_PMID 749711 HCC1187 breast NS NS NS carcinoma ductal_carcinoma NS NS 665 ENST00000360863.10(RGS22):r.1_3555::ENST00000369518.1(SYCP1):r.2100_3452 8 - 197199 RGS22 22 99981937 99981937 100106116 100106116 1 + 212470 SYCP1_ENST00000369518 24 114944339 114944339 114995367 114995367 Inferred Breakpoint 20033038 ``` **Parsing** From the TSV file, we're mainly interested in the following columns: * `SAMPLE_ID` * `PRIMARY_SITE` * `PRIMARY_HISTOLOGY` * `HISTOLOGY_SUBTYPE_1` * `FUSION_ID` * `TRANSLOCATION_NAME` * `PUBMED_PMID` {% hint style="info" %} For all the histologies and sites, we replace all the underlines with spaces. `salivary_gland` would become `salivary gland`. {% endhint %} **Parsing** To create the gene fusion entries in Illumina Connected Annotations, we perform the following on each row in the TSV file: * Group all entries by FUSION\_ID * Using all the entries related to this FUSION\_ID: * Collect all the PubMed IDs * Tally the number of observed sample IDs * Grab the HGVS r. notation (should not change throughout the FUSION\_ID) * Tally the number of samples observed for each histology * Tally the number of samples observed for each site * Extract the transcript IDs from the HGVS notation and lookup the associated gene symbols **Aggregating Histologies & Sites** [Aggregating Histologies & Sites](#aggregating-histologies--sites) was previously described in the small variants section. #### Known Issues {% hint style="warning" %} **Known Issues** There are some issues with the HGVS RNA notation: * For coding transcripts, HGVS numbering should use CDS coordinates. Right now COSMIC is using cDNA coordinates for all their fusions. {% endhint %} #### Download URL **GRCh37** * [CosmicFusionExport.tsv.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh37/cosmic/v96/CosmicFusionExport.tsv.gz) **GRCh38** * [CosmicFusionExport.tsv.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh38/cosmic/v96/CosmicFusionExport.tsv.gz) #### JSON Output ```json "cosmicGeneFusions":[ { "id":"COSF881", "numSamples":6, "geneSymbols":[ "MYB", "NFIB" ], "hgvsr":"ENST00000341911.5(MYB):r.1_2368::ENST00000397581.2(NFIB):r.2592_3318", "histologies":[ { "name":"adenoid cystic carcinoma", "numSamples":6 } ], "sites":[ { "name":"salivary gland (submandibular)", "numSamples":1 }, { "name":"salivary gland (parotid)", "numSamples":1 }, { "name":"salivary gland (nasal cavity)", "numSamples":1 }, { "name":"breast", "numSamples":3 } ], "pubMedIds":[ 19841262 ] } ] ``` | Field | Type | Notes | | ----------- | :----------: | -------------------------------------- | | id | string | COSMIC fusion ID | | numSamples | int | | | geneSymbols | string array | 5' gene & 3' gene | | hgvsr | string | HGVS RNA translocation fusion notation | | histologies | count array | phenotypic descriptions | | sites | count array | tissue types | | pubMedIds | int array | PubMed IDs | **Count** | Field | Type | Notes | | ---------- | :----: | ----------- | | name | string | description | | numSamples | int | | ### Cancer Gene Census #### TSV Extraction **Example** ```scss GENE_NAME CELL_TYPE PUBMED_PMID HALLMARK IMPACT DESCRIPTION CELL_LINE PRDM16 18496560 role in cancer oncogene oncogene PRDM16 16015645 role in cancer fusion fusion ``` **Parsing** To extract information about TSGs and oncogenes, the data based on the "role in cancer" attribute is filtered. For tumor suppressor genes, rows with the value "TSG" and for oncogenes, rows with the value "oncogene" are filtered. Some genes have both "TSG/oncogene" as their role, which indicates that they can act as both. **Columns** Only following columns are needed to gather required roles in cancer: * `GENE_NAME` * `IMPACT` * `HALLMARK` **Possible Roles in Cancer** The file contained following number of instances for each role type | Role in cancer | Total Instances | | -------------- | :-------------: | | fusion | 149 | | TSG | 195 | | oncogene | 181 | | Total | 525 | #### CSV Extraction COSMIC Tiers are extracted from `cancer_gene_census.csv` file: ```scss Gene Symbol,Name,Entrez GeneId,Genome Location,Tier,Hallmark,Chr Band,Somatic,Germline,Tumour Types(Somatic),Tumour Types(Germline),Cancer Syndrome,Tissue Type,Molecular Genetics,Role in Cancer,Mutation Types,Translocation Partner,Other Germline Mut,Other Syndrome,COSMIC ID,cosmic gene name,Synonyms "AR","Androgen Receptor ","367","X:67544036-67730619","1","Yes","Xq12","yes","yes","prostate","","","E","Dom","oncogene","Mis","","yes ","Androgen insensitivity, Hypospadias 1, X-linked, Spinal and bulbar muscular atrophy of Kennedy ","COSG292497","AR","367,AIS,AR,DHTR,ENSG00000169083.16,HUMARA,NR3C4,P10275,SBMA,SMAX1" "FH","fumarate hydratase","2271","1:241497603-241519761","1","","1q43","","yes","","leiomyomatosis, renal","hereditary leiomyomatosis and renal cell cancer","E, M","Rec","TSG","Mis, N, F","","","","COSG255037","FH","2271,ENSG00000091483.6,FH,P07954" "ALK","anaplastic lymphoma kinase (Ki-1)","238","2:29192774-29921566","1","Yes","2p23.2","yes","yes","ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumour, Spitzoid tumour","neuroblastoma","familial neuroblastoma","L, E, M","Dom","oncogene, fusion","T, Mis, A","NPM1, TPM3, TFG, TPM4, ATIC, CLTC, MSN, RNF213, CARS, EML4, KIF5B, C2orf22, DCTN1, HIP1, TPR, RANBP2, PPFIBP1, SEC31A, STRN, VCL, C2orf44, KLC1","","","COSG383409","ALK","238,ALK,CD246,ENSG00000171094.17,Q9UM73" "APC","adenomatous polyposis of the colon gene","324","5:112737888-112846239","1","Yes","5q22.2","yes","yes","colorectal, pancreatic, desmoid, hepatoblastoma, glioma, other CNS","colorectal, pancreatic, desmoid, hepatoblastoma, glioma, other CNS","adenomatous polyposis coli; Turcot syndrome","E, M, O","Rec","TSG","D, Mis, N, F, S","","","","COSG208824","APC","324,APC,DP2,DP2.5,DP3,ENSG00000134982.16,P25054,PPP1R46" ``` **Columns** Only following columns are needed to gather required roles in cancer: * `Gene Symbol` * `Tier` First the tiers are found from the CSV; based on gene symbols, the tiers' information is added while parsing through the TSV #### Known Issues None #### Download URL * [Cancer\_Gene\_Census\_Hallmarks\_Of\_Cancer.tsv.gz](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh38/cosmic/v99/Cancer_Gene_Census_Hallmarks_Of_Cancer.tsv.gz) * [cancer\_gene\_census.csv](https://cancer.sanger.ac.uk/cosmic/file_download/GRCh38/cosmic/v99/cancer_gene_census.csv) #### JSON output ```json { "name": "PRDM16", "ensemblGeneId": "ENSG00000142611", "ncbiGeneId": "63976", "hgncId": 14000, "cosmic": { "tier": 1, "roleInCancer": [ "oncogene", "fusion" ] } } ``` | Field | Type | Notes | | ------------ | :----------: | ----------------------- | | roleInCancer | string array | Possible roles in caner | | tier | number | Cosmic tiers \[1, 2] | ### Building the supplementary files You can generate COSMIC supplementary annotation files if you have COSMIC account credentials. 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