Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
J Hepatol. 2018 May;68(5):959-969. doi: 10.1016/j.jhep.2018.01.009. Epub 2018 Jan 31.
BACKGROUND & AIMS: 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.
胆道癌（BTC）在临床上和病理学上具有异质性，对治疗反应不佳。基因组分析可以更清楚地了解其致癌机制、分类和治疗策略。我们对 BTC 进行了大规模的基因组测序分析，以研究其体细胞和种系驱动事件，并描述其基因组特征。
我们分析了来自日本和意大利人群的 412 个 BTC 样本，其中 107 个进行了全外显子组测序（WES），39 个进行了全基因组测序（WGS），另外 266 个进行了靶向测序。这些亚型包括 136 例肝内胆管癌（ICC）、101 例远端胆管癌（DCC）、109 例肝门周围型胆管癌（PHC）和 66 例胆囊或胆管癌（GBC/CDC）。我们鉴定了 BTC 中的体细胞改变，并寻找驱动基因，发现了癌症易感基因的致病性种系变异。我们通过结合体细胞突变模式和表观遗传特征预测了 BTC 的细胞起源。
我们鉴定了 32 个显著且常见的突变基因，包括 TP53、KRAS、SMAD4、NF1、ARID1A、PBRM1 和 ATR，其中一些基因的突变与患者的预后不良有关。在 7q22.1 处的 MUC17 缺失对患者的预后有影响。利用 WGS 和表观遗传特征进行的细胞起源预测表明，与肝炎相关的 ICC 起源于肝细胞。在 11%（16/146）的 BTC 患者中检测到 BRCA1、BRCA2、RAD51D、MLH1 或 MSH2 等癌症易感基因的有害种系突变。
BTC 具有独特的遗传特征，包括体细胞事件和种系易感性。这些发现可用于根据遗传信息为 BTC 建立治疗和诊断策略。
我们在此分析了来自日本和意大利人群的 412 个 BTC 样本的基因组特征。共鉴定出 32 个显著且常见的突变基因，其中一些基因的突变与患者的预后不良有关，包括在 7q22.1 处的 MUC17 缺失。利用 WGS 和表观遗传特征进行的细胞起源预测表明，与肝炎相关的 ICC 起源于肝细胞。在 11%的 BTC 患者中检测到癌症易感基因的有害种系突变。BTC 具有独特的遗传特征，包括体细胞事件和种系易感性。
