Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
Department of Clinical Genomics, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
Jpn J Clin Oncol. 2021 May 28;51(6):886-894. doi: 10.1093/jjco/hyab026.
The attention on mismatch repair-deficient (dMMR) gastric cancer has increased in this era of anti-PD-1 blockade therapy; however, the prevalence and molecular genetics of patients with dMMR gastric cancer have not been completely investigated.
Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary gastric cancers of 513 consecutive patients. Genetic and/or epigenetic alterations of the MMR genes were also investigated.
Loss of expression of one or more MMR proteins was observed in 58 patients (11.3%); 54 patients showed loss of MLH1/PMS2, 3 patients showed loss of MLH1/PMS2/MSH6 and 1 patient showed loss of PMS2 alone. Among these 58 patients, 55 showed hypermethylation of the promoter region of MLH1. Genetic testing revealed that the remaining three patients had Lynch syndrome (n = 1) or Lynch-like syndrome (n = 2). A total of 15 patients (25.9% of all patients with dMMR gastric cancer and 2.9% of all patients with gastric cancer), including 11 patients with stage I-III dMMR gastric cancer who had recurrence and 4 patients with stage IV dMMR gastric cancer, are potential candidates for the use of anti-PD-1 blockades.
This is the first study to investigate the frequency and molecular genetic mechanisms of dMMR gastric cancer comprehensively, focusing on the benefit of using PD-1 blockades. Our observations will be beneficial in the clinical practice of metastatic gastric cancer.
在抗 PD-1 阻断治疗时代，人们对错配修复缺陷（dMMR）胃癌的关注度增加；然而，dMMR 胃癌患者的患病率和分子遗传学尚未得到全面研究。
对 513 例连续接受手术切除的原发性胃癌患者的福尔马林固定石蜡包埋切片进行 MMR 蛋白（MLH1、MSH2、MSH6 和 PMS2）免疫组化染色。还研究了 MMR 基因的遗传和/或表观遗传改变。
58 例（11.3%）患者观察到一种或多种 MMR 蛋白表达缺失；54 例患者 MLH1/PMS2 缺失，3 例患者 MLH1/PMS2/MSH6 缺失，1 例患者 PMS2 单独缺失。在这 58 例患者中，55 例患者 MLH1 启动子区域出现高甲基化。基因检测显示其余 3 例患者分别患有 Lynch 综合征（n=1）或 Lynch 样综合征（n=2）。共有 15 例（所有 dMMR 胃癌患者的 25.9%和所有胃癌患者的 2.9%），包括 11 例 I-III 期 dMMR 胃癌患者复发和 4 例 IV 期 dMMR 胃癌患者，可能是使用 PD-1 阻断剂的候选者。
这是首次全面研究 dMMR 胃癌的频率和分子遗传学机制，并重点关注使用 PD-1 阻断剂的获益。我们的观察结果将有助于转移性胃癌的临床实践。
