Yamamoto Hiroyuki, Watanabe Yoshiyuki, Maehata Tadateru, Morita Ryo, Yoshida Yoshihito, Oikawa Ritsuko, Ishigooka Shinya, Ozawa Shun-Ichiro, Matsuo Yasumasa, Hosoya Kosuke, Yamashita Masaki, Taniguchi Hiroaki, Nosho Katsuhiko, Suzuki Hiromu, Yasuda Hiroshi, Shinomura Yasuhisa, Itoh Fumio
Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroshi Yasuda, Fumio Itoh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
World J Gastroenterol. 2014 Apr 14;20(14):3927-37. doi: 10.3748/wjg.v20.i14.3927.
Gastric cancer (GC) is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs. Recent studies using next-generation sequencing (NGS) have revealed a number of potential cancer-driving genes in GC. Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4, a member of the cadherin gene family. Mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) have been found in 47% of GCs. Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC. Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery, such as DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs and microRNAs. Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings. The anti-human epidermal growth receptor 2 (HER2) antibody trastuzumab has led to an era of personalized therapy in GC. In addition, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor (VEGFR)-2, is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after first-line chemotherapy. Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets, as well as useful biomarkers. In this review, we will summarize the recent advances in the understanding of the molecular pathogenesis of GC, focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.
胃癌（GC）是最常见的恶性肿瘤之一，仍然是全球癌症相关死亡的第二大主要原因。人们对基因和表观遗传改变在胃癌中所起的作用有了越来越深入的了解。最近使用下一代测序（NGS）的研究揭示了胃癌中一些潜在的致癌驱动基因。胃癌的全外显子测序已确定染色质重塑基因ARID1A中的复发性体细胞突变以及细胞粘附基因FAT4（钙粘蛋白基因家族的成员）的改变。在47%的胃癌中发现了染色质重塑基因（ARID1A、MLL3和MLL）的突变。全基因组测序和全转录组测序分析也发现了胃癌中的新改变。最近对癌症表观遗传学的研究揭示了参与表观遗传机制的基因广泛改变，如DNA甲基化、组蛋白修饰、核小体定位、非编码RNA和微小RNA。胃癌分子研究的最新进展已导致将新的诊断和治疗策略引入临床。抗人表皮生长因子受体2（HER2）抗体曲妥珠单抗开创了胃癌个性化治疗的时代。此外，雷莫西尤单抗是一种靶向血管内皮生长因子受体（VEGFR）-2的单克隆抗体，是第一种在一线化疗后进展的晚期胃癌患者中作为单药治疗显示出生存益处的生物治疗药物。使用NGS系统地鉴定胃癌中的基因改变是一种有前途的方法，在研究胃癌的发病机制、鉴定新的治疗靶点以及有用的生物标志物方面具有巨大潜力。在这篇综述中，我们将总结对胃癌分子发病机制理解的最新进展，重点关注这些基因和表观遗传改变作为诊断生物标志物和新治疗靶点的潜在用途。
