Institute of Digestive Disease and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong. Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
Institute of Digestive Disease and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong. Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
Cancer Res. 2016 Apr 1;76(7):1724-32. doi: 10.1158/0008-5472.CAN-15-2443. Epub 2016 Feb 8.
Gastric cancer is not a single disease, and its subtype classification is still evolving. Next-generation sequencing studies have identified novel genetic drivers of gastric cancer, but their use as molecular classifiers or prognostic markers of disease outcome has yet to be established. In this study, we integrated somatic mutational profiles and clinicopathologic information from 544 gastric cancer patients from previous genomic studies to identify significantly mutated genes (SMG) with prognostic relevance. Gastric cancer patients were classified into regular (86.8%) and hypermutated (13.2%) subtypes based on mutation burden. Notably, TpCpW mutations occurred significantly more frequently in regular, but not hypermutated, gastric cancers, where they were associated with APOBEC expression. In the former group, six previously unreported (XIRP2, NBEA, COL14A1, CNBD1, ITGAV, and AKAP6) and 12 recurrent mutated genes exhibited high mutation prevalence (≥3.0%) and an unexpectedly higher incidence of nonsynonymous mutations. We also identified two molecular subtypes of regular-mutated gastric cancer that were associated with distinct prognostic outcomes, independently of disease staging, as confirmed in a distinct patient cohort by targeted capture sequencing. Finally, in diffuse-type gastric cancer, CDH1 mutation was found to be associated with shortened patient survival, independently of disease staging. Overall, our work identified previously unreported SMGs and a mutation signature predictive of patient survival in newly classified subtypes of gastric cancer, offering opportunities to stratify patients into optimal treatment plans based on molecular subtyping. Cancer Res; 76(7); 1724-32. ©2016 AACR.
胃癌不是一种单一的疾病，其亚型分类仍在不断发展。下一代测序研究已经确定了胃癌的新的遗传驱动因素，但它们作为分子分类器或疾病预后的标志物的用途尚未得到确立。在这项研究中，我们整合了 544 名来自先前基因组研究的胃癌患者的体细胞突变谱和临床病理信息，以确定具有预后相关性的显著突变基因（SMG）。根据突变负担，将胃癌患者分为常规（86.8%）和超突变（13.2%）亚型。值得注意的是，TpCpW 突变在常规但非超突变的胃癌中发生的频率明显更高，在后者中与 APOBEC 表达相关。在前一组中，六个以前未报道的（XIRP2、NBEA、COL14A1、CNBD1、ITGAV 和 AKAP6）和 12 个反复突变的基因表现出高突变普遍性（≥3.0%）和非同义突变的发生率异常高。我们还确定了两种与不同预后结果相关的常规突变型胃癌的分子亚型，这与通过靶向捕获测序在另一组患者中得到证实的独立于疾病分期的结果一致。最后，在弥漫型胃癌中，CDH1 突变与患者生存时间缩短有关，这与疾病分期无关。总的来说，我们的工作确定了以前未报道的 SMG 和一个预测新分类的胃癌亚型患者生存的突变特征，为基于分子亚型对患者进行分层以制定最佳治疗计划提供了机会。Cancer Res; 76(7); 1724-32. ©2016 AACR.
