Ge Sai, Li Beifang, Li Yanyan, Li Zhongwu, Liu Zhentao, Chen Zuhua, Wu Jian, Gao Jing, Shen Lin
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and InstituteBeijing 100142, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital and InstituteBeijing 100142, China.
Am J Cancer Res. 2017 Jul 1;7(7):1540-1553. eCollection 2017.
Gastric cancer (GC) remains the second tumor caused death threat worldwide, and personalized medicine for GC is far from expectation. Finding novel, recurrently mutated genes through next-generation sequencing (NGS) is a powerful and productive approach. However, previous genomic data for GC are based on surgical resected samples while a large proportion of advanced gastric cancer (AGC) patients have already missed the chance for operation. The aim of this study is to assess frequent genomic alteration in AGC via biopsy samples. Here we performed targeted genomic sequencing of 78 AGC patients' tumor biopsies along with matched lymphocyte samples based on a 118 cancer related gene panel. In total, we observed 301 somatic nonsynonymous genomic alterations in 92 different genes, as well as 37 copy number gain events among 15 different genes (fold change 2-12), and validated the fold changes of copy number gains with IHC and FISH test showed an accuracy of 81.8%. Previously reported driver genes for gastric cancer (, and ), and several unreported mutations (, and ) showed high non-silent mutation prevalence (7.7%-34.6%). When comparing intestinal-type gastric cancer (IGC) with diffuse-type gastric cancer (DGC), and appear to be more frequently mutated in IGC (=0.028 and =0.023, respectively), whereas and mutations are not observed in IGC, but have 12.8%, 7.7% and 7.7% mutation rates, respectively, in DGC patients. Patients with one or more mutations in adherens junction pathway ( and ) or TGF-β signaling pathway () showed significantly better overall survival (=0.007 and =0.014, respectively), consistent with The Cancer Genome Atlas (TCGA) cohort data. Importantly, 57 (73.1%) patients harbored at least one genomic alteration with potential treatments, making NGS-based drug target screening a viable option for AGC patients. Our study established a comprehensive genomic portrait of AGC, and identified several mutation signatures highly associated with clinical features, survival outcomes, which may be used to design future personalized treatments.
胃癌（GC）仍是全球导致死亡威胁的第二大肿瘤，而针对GC的个性化医疗远未达到预期。通过下一代测序（NGS）发现新的、反复突变的基因是一种强大且有效的方法。然而，先前的GC基因组数据基于手术切除样本，而很大一部分晚期胃癌（AGC）患者已经错失手术机会。本研究的目的是通过活检样本评估AGC中频繁的基因组改变。在此，我们基于一个包含118个癌症相关基因的面板，对78例AGC患者的肿瘤活检样本以及匹配的淋巴细胞样本进行了靶向基因组测序。总共，我们在92个不同基因中观察到301个体细胞非同义基因组改变，以及15个不同基因中的37个拷贝数增加事件（倍数变化为2至12），并通过免疫组化（IHC）和荧光原位杂交（FISH）试验验证了拷贝数增加的倍数变化，显示准确率为81.8%。先前报道的胃癌驱动基因（ ，以及 ），以及几个未报道的突变（ ，以及 ）显示出较高的非沉默突变发生率（7.7% - 34.6%）。当比较肠型胃癌（IGC）与弥漫型胃癌（DGC）时， 和 在IGC中似乎更频繁发生突变（分别为 = 0.028和 = 0.023），而在IGC中未观察到 和 突变，但在DGC患者中分别有12.8%、7.7%和7.7%的突变率。在黏着连接通路（ 和 ）或转化生长因子 - β信号通路（ ）中有一个或多个突变的患者总体生存率显著更好（分别为 = 0.007和 = 0.014），这与癌症基因组图谱（TCGA）队列数据一致。重要的是，57例（73.1%）患者至少有一个具有潜在治疗方法的基因组改变，这使得基于NGS的药物靶点筛选成为AGC患者的一个可行选择。我们的研究建立了AGC的全面基因组图谱，并鉴定了几个与临床特征、生存结果高度相关的突变特征，这可能用于设计未来的个性化治疗方案。
