Yu Haipeng, Xu Yan, Gao Wei, Li Mei, He Ji'an, Deng Xiaoqian, Xing Wenge
Department of Interventional Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Front Oncol. 2022 Aug 22;12:930611. doi: 10.3389/fonc.2022.930611. eCollection 2022.
Biliary tract cancer (BTC) is an uncommon but highly lethal malignancy with poor clinical outcomes. To promote the development of precision medicine for BTC, uncovering its genomic profile becomes particularly important. However, studies on the genomic feature of Chinese BTC patients remain insufficient.
A total of 382 Chinese patients with BTC were enrolled in this study, including 71 with intrahepatic cholangiocarcinoma (ICC), 194 with extrahepatic cholangiocarcinoma (ECC), and 117 with gallbladder carcinoma (GBC). Genetic testing was performed by utilizing the next-generation sequencing (NGS) of 499 cancer-related genes and the results were compared to those of Western BTC patients (MSKCC cohorts).
The most prevalent genes were (51.6%), (25.9%), (24.6%), (17%), (15.2%), (14.9%), (14.9%), (14.1%), and (13.9%) in Chinese BTC patients. , and were more prevalent in GBC, ECC, and ICC, respectively. In addition, 10.5% of Chinese BTC patients harbored pathogenic or likely pathogenic (P/LP) germline alterations in 41 genes, which were mainly related to DNA damage repair (DDR). Additionally, the genomic features of Chinese and Western BTC tumors were similar, with the exception of the notable difference in the prevalence of , , , , and . Notably, Chinese BTC patients had high prevalence (57.1%) of actionable alterations, especially for those with ECC, and half (192/382) of them had somatic DDR alterations, with the prevalence of deleterious ones being significantly higher than their Western counterparts. Twenty-three percent of patients had a higher tumor mutational burden (TMB-H, over 10 mutations/MB), and TMB was significantly higher in those with deleterious DDR alterations and/or microsatellite instability-high. The most common mutational signature in BTC patients was Signature 1, and interestingly, Signatures 1, 4, and 26 were significantly associated with higher TMB level, but not with the survival of patients who had received immunotherapy in pan-cancer.
Our study elaborated the distinct germline and somatic genomic characteristics of Chinese BTC patients and identified clinically actionable alterations, highlighting the possibility for the development and application of precision medicine.
胆管癌（BTC）是一种罕见但致死率很高的恶性肿瘤，临床预后较差。为推动BTC精准医学的发展，揭示其基因组特征变得尤为重要。然而，关于中国BTC患者基因组特征的研究仍然不足。
本研究共纳入382例中国BTC患者，其中71例为肝内胆管癌（ICC），194例为肝外胆管癌（ECC），117例为胆囊癌（GBC）。通过对499个癌症相关基因进行二代测序（NGS）进行基因检测，并将结果与西方BTC患者（MSKCC队列）的结果进行比较。
中国BTC患者中最常见的基因依次为（51.6%）、（25.9%）、（24.6%）、（17%）、（15.2%）、（14.9%）、（14.9%）、（14.1%）和（13.9%）。、和分别在GBC、ECC和ICC中更为常见。此外，10.5%的中国BTC患者在41个基因中存在致病性或可能致病性（P/LP）种系改变，这些改变主要与DNA损伤修复（DDR）相关。此外，中国和西方BTC肿瘤的基因组特征相似，但、、、和的发生率存在显著差异。值得注意的是，中国BTC患者中可操作改变的发生率较高（57.1%），尤其是ECC患者，其中一半（192/382）存在体细胞DDR改变，有害改变的发生率显著高于西方患者。23%的患者肿瘤突变负荷较高（TMB-H，超过10个突变/MB），DDR改变有害和/或微卫星高度不稳定的患者TMB显著更高。BTC患者中最常见的突变特征是特征1，有趣的是，特征1、4和26与较高的TMB水平显著相关，但与泛癌中接受免疫治疗患者的生存无关。
我们的研究阐述了中国BTC患者独特的种系和体细胞基因组特征，并确定了临床上可操作的改变，突出了精准医学发展和应用的可能性。
