Biomaterial Database

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. 2018

Christopher P Wardell, and Masashi Fujita, and Toru Yamada, and Michele Simbolo, and Matteo Fassan, and Rosa Karlic, and Paz Polak, and Jaegil Kim, and Yutaka Hatanaka, and Kazuhiro Maejima, and Rita T Lawlor, and Yoshitsugu Nakanishi, and Tomoko Mitsuhashi, and Akihiro Fujimoto, and Mayuko Furuta, and Andrea Ruzzenente, and Simone Conci, and Ayako Oosawa, and Aya Sasaki-Oku, and Kaoru Nakano, and Hiroko Tanaka, and Yujiro Yamamoto, and Kubo Michiaki, and Yoshiiku Kawakami, and Hiroshi Aikata, and Masaki Ueno, and Shinya Hayami, and Kunihito Gotoh, and Shun-Ichi Ariizumi, and Masakazu Yamamoto, and Hiroki Yamaue, and Kazuaki Chayama, and Satoru Miyano, and Gad Getz, and Aldo Scarpa, and Satoshi Hirano, and Toru Nakamura, and Hidewaki Nakagawa

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

Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. 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. We analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features. 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% (16/146) of BTC patients. 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 populations. A total of 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 patients with BTC. BTCs have distinct genetic features including somatic events and germline predisposition.

UI	MeSH Term	Description	Entries
D007558	Italy	A country in southern Europe, a peninsula extending into the central Mediterranean Sea, northeast of Tunisia. The capital is Rome.	Sardinia
D007564	Japan	A country in eastern Asia, island chain between the North Pacific Ocean and the Sea of Japan, east of the Korean Peninsula. The capital is Tokyo.	Bonin Islands
D009154	Mutation	Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.	Mutations
D009857	Oncogenes	Genes whose gain-of-function alterations lead to NEOPLASTIC CELL TRANSFORMATION. They include, for example, genes for activators or stimulators of CELL PROLIFERATION such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of "v-" before oncogene symbols indicates oncogenes captured and transmitted by RETROVIRUSES; the prefix "c-" before the gene symbol of an oncogene indicates it is the cellular homolog (PROTO-ONCOGENES) of a v-oncogene.	Transforming Genes,Oncogene,Transforming Gene,Gene, Transforming,Genes, Transforming
D011379	Prognosis	A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations.	Prognostic Factor,Prognostic Factors,Factor, Prognostic,Factors, Prognostic,Prognoses
D004252	DNA Mutational Analysis	Biochemical identification of mutational changes in a nucleotide sequence.	Mutational Analysis, DNA,Analysis, DNA Mutational,Analyses, DNA Mutational,DNA Mutational Analyses,Mutational Analyses, DNA
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000073336	Whole Genome Sequencing	Techniques to determine the entire sequence of the GENOME of an organism or individual.	Complete Genome Sequencing,Genome Sequencing, Complete,Genome Sequencing, Whole,Sequencing, Complete Genome,Sequencing, Whole Genome
D000073359	Exome Sequencing	Techniques used to determine the sequences of EXONS of an organism or individual.	Complete Exome Sequencing,Complete Transcriptome Sequencing,Whole Exome Sequencing,Whole Transcriptome Sequencing,Complete Exome Sequencings,Exome Sequencing, Complete,Exome Sequencing, Whole,Exome Sequencings, Complete,Sequencing, Complete Exome,Sequencing, Complete Transcriptome,Sequencing, Exome,Sequencing, Whole Exome,Sequencing, Whole Transcriptome,Transcriptome Sequencing, Complete,Transcriptome Sequencing, Whole,Transcriptome Sequencings, Complete
D001661	Biliary Tract Neoplasms	Tumors or cancer in the BILIARY TRACT including the BILE DUCTS and the GALLBLADDER.	Biliary Tract Cancer,Cancer of Biliary Tract,Cancer of the Biliary Tract,Neoplasms, Biliary Tract,Biliary Tract Cancers,Biliary Tract Neoplasm,Cancer, Biliary Tract,Cancers, Biliary Tract,Neoplasm, Biliary Tract