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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.
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.
Cell-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.
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.
Shares MSH2, MLH1, Lynch syndrome, BRCA1 / BRCA2 (HRD).
Shares MSH2, MLH1, dMMR (mismatch repair deficiency by IHC), Lynch syndrome.
Shares MSH2, MLH1, dMMR (mismatch repair deficiency by IHC), Lynch syndrome.
Shares MSH2, MLH1, dMMR (mismatch repair deficiency by IHC), Lynch syndrome.
Shares Homologous recombination deficiency (HRD), BRCA1 / BRCA2 (HRD), Biliary tract cancer (cholangiocarcinoma), Gallbladder cancer.
Shares ARID1A, SMAD4, Biliary tract cancer (cholangiocarcinoma), Gallbladder cancer.
Shares MLH1, dMMR (mismatch repair deficiency by IHC), Lynch syndrome.
Shares ARID1A, SMAD4, Gallbladder cancer.