# Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations

Source: https://onco.cc/key-papers/paper-wardell-biliary-drivers-germline-j-hepatol-2018/  
OnCo record `paper-wardell-biliary-drivers-germline-j-hepatol-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Journal of Hepatology
- Year: 2018
- DOI: 10.1016/j.jhep.2018.01.009
- Authors: Wardell CP, Fujita M, Yamada T, et al.
- 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.
- What it means: 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.

## Sources

- Wardell et al., J Hepatol 2018: genomic characterisation of 412 biliary tract cancers: https://doi.org/10.1016/j.jhep.2018.01.009
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29360550/

## Connected records

- cancers: [Biliary tract cancer (all types)](https://onco.cc/cancers/biliary-tract-cancer/), [Biliary tract cancer (cholangiocarcinoma)](https://onco.cc/cancers/cholangiocarcinoma/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/)
- targets: [ARID1A](https://onco.cc/targets/arid1a/), [ATR](https://onco.cc/targets/atr/), [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [MLH1](https://onco.cc/targets/mlh1/), [MSH2](https://onco.cc/targets/msh2/), [NF1 (neurofibromin)](https://onco.cc/targets/nf1/), [RAD51D](https://onco.cc/targets/rad51d/), [SMAD4](https://onco.cc/targets/smad4/)
- terms: [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/)
- biomarkers: [dMMR (mismatch repair deficiency by IHC)](https://onco.cc/biomarkers/dmmr-ihc/)

---
JSON: https://onco.cc/api/v1/entities/paper-wardell-biliary-drivers-germline-j-hepatol-2018.json