Zhang Bo-Lun, Ji Xu, Yu Ling-Xiang, Gao Yuan, Xiao Chao-Hui, Liu Jia, Zhao De-Xi, Le Yi, Diao Guang-Hao, Sun Jia-Yi, Li Gao-Hua, Lei Guang-Lin, Yu Peng, Wang Rui-Lan, Wu Jian-Zhong, Yang Peng-Hui, Yan Jin, Li Jing-Yu, Xu Jia-Jia, Zhang Shao-Geng, Tian Hu
Department of General Surgery, Clinical Medical College of Weifang Medical University, Weifang, Shandong 261042, P.R. China.
Department of Hepatobiliary Surgery, 302 Military Hospital of China, Beijing 100039, P.R. China.
Oncol Lett. 2018 Nov;16(5):6003-6012. doi: 10.3892/ol.2018.9371. Epub 2018 Aug 29.
Liver and biliary cancers are highly lethal cancer types lacking effective treatments. The somatic mutations, particularly those with low mutant allele frequencies, in Chinese patients with liver and biliary cancer have not been profiled, and the frequency of patients benefiting from targeted therapy has not been studied. The present study evaluated the tumor tissues of 45 Chinese patients with hepatocellular carcinoma (HCC) and 12 Chinese patients with biliary tract cancer (BTC) by targeted next generation sequencing, with an average coverage of 639×, to identify alterations in 372 cancer-related genes. A total of 263 variants were identified in 139 genes, with 85.6% of these variants not previously reported in the Catalogue Of Somatic Mutations In Cancer database, and the mutation profile was different from the current datasets, including The Cancer Genome Atlas dataset and the National Cancer Center Japan (NCC_JP) dataset. Patients with hepatitis B virus (HBV) infection harbored more mutations than those without HBV infection, and the mutations in HBV carriers occurred preferentially in genes involved in vascular endothelial growth factor signaling pathways. Mutations in fibroblast growth factor and RAS signaling pathways were enriched in patients with cirrhosis, and alterations in interleukin and transforming growth factor signaling pathways were more frequently identified in individuals with abnormal bilirubin expression. Of all the patients, 7% exhibited variants in the target of sorafenib, and 42% harbored variants in the targets of drugs that have been approved to treat other types of cancer. These findings indicate diverse HCC/BTC variants patterns in different populations, and that the mutation load and patterns are correlated with clinical features. Further clinical studies are now warranted to evaluate the efficacies of other targeted drugs besides sorafenib in the treatment of patients with liver and biliary cancer.
肝癌和胆管癌是缺乏有效治疗方法的高致死性癌症类型。中国肝癌和胆管癌患者的体细胞突变，尤其是那些突变等位基因频率较低的突变，尚未进行分析，且受益于靶向治疗的患者频率也未得到研究。本研究通过靶向二代测序对45例中国肝细胞癌（HCC）患者和12例中国胆管癌（BTC）患者的肿瘤组织进行评估，平均覆盖度为639×，以鉴定372个癌症相关基因的改变。在139个基因中总共鉴定出263个变异，其中85.6%的变异在癌症体细胞突变目录数据库中未曾报道，且突变谱与当前数据集不同，包括癌症基因组图谱数据集和日本国立癌症中心（NCC_JP）数据集。乙型肝炎病毒（HBV）感染患者比未感染HBV的患者携带更多突变，且HBV携带者中的突变优先发生在参与血管内皮生长因子信号通路的基因中。成纤维细胞生长因子和RAS信号通路的突变在肝硬化患者中富集，白细胞介素和转化生长因子信号通路的改变在胆红素表达异常的个体中更频繁地被鉴定出来。在所有患者中，7%的患者在索拉非尼的靶点中表现出变异，42%的患者在已获批用于治疗其他类型癌症的药物靶点中携带变异。这些发现表明不同人群中HCC/BTC变异模式多样，且突变负荷和模式与临床特征相关。现在有必要进行进一步的临床研究，以评估除索拉非尼之外的其他靶向药物治疗肝癌和胆管癌患者的疗效。
