{"entity":{"id":"paper-wardell-biliary-drivers-germline-j-hepatol-2018","kind":"paper","name":"Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations","aka":[],"tldr":"Sequencing 412 Japanese and Italian biliary cancers, including 66 gallbladder and cystic duct tumours, found 32 driver genes and, unexpectedly, an inherited cancer-predisposing mutation in about one in nine patients.","summary":"412 biliary tract cancer samples from Japanese and Italian populations were analysed, 107 by whole-exome sequencing, 39 by whole-genome sequencing and 266 by targeted sequencing: 136 intrahepatic, 101 distal and 109 perihilar cholangiocarcinomas and 66 gallbladder or cystic duct cancers. Thirty-two significantly and commonly mutated genes were identified, including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1 and ATR, some of which negatively affected prognosis, and a novel deletion of MUC17 at 7q22.1 affected prognosis.\n\nCell-of-origin predictions using whole-genome and epigenetic features suggested a hepatocyte origin for hepatitis-related intrahepatic cholangiocarcinoma. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1 or MSH2 were detected in 11% (16 of 146) of patients.","asOf":"2026-09-24","links":[{"label":"Wardell et al., J Hepatol 2018: genomic characterisation of 412 biliary tract cancers","url":"https://doi.org/10.1016/j.jhep.2018.01.009"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29360550/"}],"tags":[],"related":[],"cancers":["gallbladder","cholangiocarcinoma","biliary-tract-cancer"],"sections":[],"technologies":[],"targets":["brca","rad51d","mlh1","msh2","smad4","arid1a","nf1","atr"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["lynch-syndrome","hrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Journal of Hepatology","year":2018,"doi":"10.1016/j.jhep.2018.01.009","pmid":"29360550","authors":"Wardell CP, Fujita M, Yamada T, et al.","paperType":"translational","findings":["32 significantly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1 and ATR.","Deleterious germline variants in BRCA1, BRCA2, RAD51D, MLH1 or MSH2 in 11% (16 of 146) of patients.","A MUC17 deletion at 7q22.1 affected prognosis."],"whatItMeans":"The germline finding is the practical lesson: a meaningful minority of biliary cancer patients carry inherited repair-gene mutations that matter for PARP inhibitor eligibility and for their relatives, which argues for germline testing alongside tumour sequencing.","caveats":["Gallbladder cancers were 66 of 412 and not always reported separately.","Germline analysis covered 146 of the patients."],"changedPractice":false,"participants":412},"route":"/key-papers/paper-wardell-biliary-drivers-germline-j-hepatol-2018/","neighbours":{"cancer":[{"id":"biliary-tract-cancer","kind":"cancer","name":"Biliary tract cancer (all types)","route":"/cancers/biliary-tract-cancer/"},{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","route":"/cancers/cholangiocarcinoma/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"}],"target":[{"id":"arid1a","kind":"target","name":"ARID1A","route":"/targets/arid1a/"},{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"mlh1","kind":"target","name":"MLH1","route":"/targets/mlh1/"},{"id":"msh2","kind":"target","name":"MSH2","route":"/targets/msh2/"},{"id":"nf1","kind":"target","name":"NF1 (neurofibromin)","route":"/targets/nf1/"},{"id":"rad51d","kind":"target","name":"RAD51D","route":"/targets/rad51d/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"}],"term":[{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"}],"biomarker":[{"id":"dmmr-ihc","kind":"biomarker","name":"dMMR (mismatch repair deficiency by IHC)","route":"/biomarkers/dmmr-ihc/"}]}}