GRCh38 · COSMIC v99

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Reference

Genomic Characterization of Biliary Tract Cancers Identifies Driver Genes and Predisposing Mutations.

Paper ID

COSP44991

Authors

Wardell CP, Fujita M, Yamada T, Simbolo M, Fassan M, Karlic R, Polak P, Kim J, Hatanaka Y, Maejima K, Lawlor RT, Nakanishi Y, Mitsuhashi T, Fujimoto A, Furuta M, Ruzzenente A, Conci S, Oosawa A, Sasaki-Oku A, Nakano K, Tanaka H, Yamamoto Y, Michiaki K, Kawakami Y, Aikata H, Ueno M, Hayami S, Gotoh K, Ariizumi SI, Yamamoto M, Yamaue H, Chayama K, Miyano S, Getz G, Scarpa A, Hirano S, Nakamura T and Nakagawa H

Affiliation

Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.

Journal

Journal of hepatology, 2018
ISSN: 1600-0641
PMID: 29360550 (view at PubMed or Europe PMC)

Abstract

Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous with poor response to treatments. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape.Methods: We analyzed 412 BTC samples from Japanese and Italian populations, with 107 whole exome sequencing (WES), 39 whole genome sequencing (WGS), and targeted sequencing of a further 266 samples. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar types (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, and found pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features.Results: We identified 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% of BTC patients.Conclusions: BTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information.We here analyzed genomic features of 412 BTC samples from Japanese and Italian population. 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes were detected in 11% of BTC patients. BTCs have distinct genetic features including somatic events and germline predisposition.

Paper Status

Curated