Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
PLoS One. 2020 Jul 23;15(7):e0236197. doi: 10.1371/journal.pone.0236197. eCollection 2020.
Genome-wide association studies of gastric cancer (GC) cases have revealed common gastric cancer susceptibility loci with low effect size. We investigated rare variants with high effect size via whole-exome sequencing (WES) of subjects with familial clustering of gastric cancer. WES of DNAs from the blood of 19 gastric cancer patients and 36 unaffected family members from 14 families with two or more gastric cancer patients were tested. Linkage analysis combined with association tests were performed using Pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) software. Based on the logarithm of odds (LOD) and permutation-based composite likelihood ratio test (CLRT) from pVAAST, MUC4 was identified as a predisposing gene (LOD P-value = 1.9×10-5; permutation-based P-value of CLRT ≤ 9.9×10-9). In a larger cohort consisting of 597 GC patients and 9,759 healthy controls genotyped with SNP array, we discovered common variants in MUC4 regions (rs148735556, rs11717039, and rs547775645) significantly associated with GC supporting the association of MUC4 with gastric cancer. And the MUC4 variants were found in higher frequency in The Cancer Genome Atlas Study (TCGA) germline samples of patients with multiple cancer types. Immunohistochemistry indicated that MUC4 was downregulated in the noncancerous gastric mucosa of subjects with MUC4 germline missense variants, suggesting that loss of the protective function of MUC4 predisposes an individual to gastric cancer. Rare variants in MUC4 can be novel gastric cancer susceptibility loci in Koreans possessing the familial clustering of gastric cancer.
全基因组关联研究已经揭示了具有低效应大小的常见胃癌易感性位点。我们通过对具有胃癌家族聚集的受试者进行外显子组测序（WES）来研究具有高效应大小的稀有变异。对来自 14 个有 2 个或更多胃癌患者的家庭的 19 名胃癌患者和 36 名无血缘关系的家庭成员的血液 DNA 进行了 WES 检测。使用 Pedigree Variant Annotation、Analysis、and Search Tool（pVAAST）软件进行连锁分析和关联测试。基于 pVAAST 的对数几率（LOD）和基于置换的复合似然比检验（CLRT），MUC4 被鉴定为易患基因（LOD P 值=1.9×10-5；置换后 CLRT 的 P 值≤9.9×10-9）。在一个由 597 名胃癌患者和 9759 名健康对照者组成的更大队列中，我们通过 SNP 芯片发现了 MUC4 区域的常见变异（rs148735556、rs11717039 和 rs547775645）与 GC 显著相关，支持 MUC4 与胃癌的关联。并且在多癌种患者的 TCGA 种系样本中发现了 MUC4 变异体的高频发生。免疫组化表明，具有 MUC4 种系错义变异的个体的非癌性胃黏膜中 MUC4 下调，提示 MUC4 保护性功能的丧失使个体易患胃癌。MUC4 中的稀有变异可能是韩国具有胃癌家族聚集的新的胃癌易感位点。
