Table_3_Comprehensive germline and somatic genomic profiles of Chinese patients with biliary tract cancer.xlsx

BackgroundBiliary 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.
MethodsA 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).
ResultsThe most prevalent genes were TP53 (51.6%), ARID1A (25.9%), KMT2C (24.6%), NCOR1 (17%), SMAD4 (15.2%), KRAS (14.9%), KMT2D (14.9%), ATM (14.1%), and APC (13.9%) in Chinese BTC patients. TP53, SMAD4, and APC 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 TP53, KRAS, IDH1, KMT2C, and SMAD4. 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.
ConclusionOur 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.

背景 胆道癌（Biliary Tract Cancer, BTC）是一类少见但致死率极高的恶性肿瘤，临床预后不佳。为推动胆道癌精准医学的发展，阐明其基因组特征显得尤为关键。然而，针对中国胆道癌患者基因组特征的相关研究仍显不足。
方法 本研究共纳入382例中国胆道癌患者，其中包括71例肝内胆管癌（Intrahepatic Cholangiocarcinoma, ICC）、194例肝外胆管癌（Extrahepatic Cholangiocarcinoma, ECC）以及117例胆囊癌（Gallbladder Carcinoma, GBC）。采用针对499个癌症相关基因的下一代测序（Next-Generation Sequencing, NGS）技术开展基因检测，并将检测结果与西方胆道癌患者队列（MSKCC队列）进行对比分析。
结果 中国胆道癌患者中最常见的突变基因为TP53（51.6%）、ARID1A（25.9%）、KMT2C（24.6%）、NCOR1（17%）、SMAD4（15.2%）、KRAS（14.9%）、KMT2D（14.9%）、ATM（14.1%）及APC（13.9%）。其中TP53、SMAD4和APC分别在GBC、ECC及ICC中突变率更高。此外，10.5%的中国胆道癌患者携带有41个基因的致病性或可能致病性（Pathogenic/Likely Pathogenic, P/LP）种系变异，此类变异主要与DNA损伤修复（DNA Damage Repair, DDR）通路相关。进一步分析显示，中国与西方胆道癌患者的基因组特征整体相似，但TP53、KRAS、IDH1、KMT2C及SMAD4的突变率存在显著差异。值得注意的是，中国胆道癌患者的可治疗性变异检出率较高（57.1%），其中ECC患者尤为突出；另有半数（192/382）患者存在体细胞DDR变异，其有害变异的检出率显著高于西方患者。23%的患者存在高肿瘤突变负荷（Tumor Mutational Burden-High, TMB-H，即每兆碱基超过10个突变），且携带有害DDR变异和/或微卫星不稳定（Microsatellite Instability-High, MSI-H）的患者TMB水平显著更高。胆道癌患者最常见的突变特征为Signature 1，有趣的是，Signature 1、4及26与更高的TMB水平显著相关，但在泛癌队列中与接受免疫治疗患者的生存无显著关联。
结论 本研究阐明了中国胆道癌患者独特的种系与体细胞基因组特征，并鉴定出临床可靶向治疗的变异，凸显了开展胆道癌精准医学研究与应用的可行性。