The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in theCDH1gene, and more rarely in theCTNNA1gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution ofCTNNA1andCTNND1germline variants to HDGC. Additionally, we also intended to compare the frequencies ofCDH1andCTNNA1(and eventuallyCTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed theCDH1gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and theCTNNA1andCTNND1genes in 208 cases with diffuse or mixed gastric cancer who had tested negative forCDH1pathogenic germline variants. A deleteriousCTNNA1germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% ofCDH1deleterious variants found by us in this setting. No deleterious variants were found inCTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenicCDH1,CTNNA1orCTNND1variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of theCTNND1gene in inherited gastric cancer predisposition is still unclear.
遗传性胃癌中特征最为明确的是遗传性弥漫性胃癌（HDGC），这是一种常染色体显性遗传综合征，其特征是弥漫性胃癌和小叶性乳腺癌的发病风险增高。HDGC主要由CDH1基因的种系致病变异引起，少数情况下由CTNNA1基因变异导致。此外，国际胃癌连锁联盟（IGCLC）指南尚未明确混合型胃癌（包含弥漫性成分）是否应纳入HDGC基因检测标准。本研究旨在评估CTNNA1和CTNND1种系变异对HDGC的贡献度。同时，我们比较了弥漫性胃癌与混合型胃癌患者中CDH1、CTNNA1（及CTNND1）种系变异的频率，以评估混合型胃癌患者是否需要进行这些基因的检测。我们对67例早发性/家族性混合型胃癌患者的CDH1基因进行了分析，并对208例CDH1种系致病变异检测呈阴性的弥漫性或混合型胃癌患者进行了CTNNA1和CTNND1基因检测。在符合2020年IGCLC标准的弥漫性胃癌患者中，发现CTNNA1有害种系变异比例为0.7%（1/141），而我们在相同条件下检测到的CDH1有害变异率为2.8%。未在CTNND1基因中发现明确致病变异，但检测到6个临床意义未明的变异。在早发性/家族性混合型胃癌的先证者中，未发现任何CDH1、CTNNA1或CTNND1致病性变异，因此目前无证据支持将此类肿瘤纳入这些基因的种系变异检测标准。CTNND1基因在遗传性胃癌易感性中的作用尚不明确。
Frequency ofCDH1, CTNNA1andCTNND1Germline Variants in Families with Diffuse and Mixed Gastric Cancer
肿瘤(癌症)患者之家