Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Department of Surgery, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire.
Gastroenterology. 2019 Jul;157(1):87-96. doi: 10.1053/j.gastro.2019.03.047. Epub 2019 Mar 29.
BACKGROUND & AIMS: Pathogenic germline variants in CDH1 are associated with risk for diffuse gastric cancer (DGC) and lobular breast cancer. The reported high incidence of DGC and limited sensitivity of endoscopy in detection have prompted recommendation for total prophylactic gastrectomy for carriers of pathogenic or likely pathogenic (PLP) germline variants of CDH1. Multigene panel tests have identified increasing numbers of carriers of PLP variants in CDH1 who lack a family history of DGC. We evaluated outcomes of endoscopic surveillance for carriers of PLP variants of CDH1 with and without family history of DGC.
Individuals from 13 families with germline PLP variants of CDH1 were evaluated at the Michigan Medicine Cancer Genetics Clinic from January 1998 through May 2018. Outcomes of esophagogastroduodenoscopy examinations, histopathology analyses, and surgery were compared between individuals with and without a family history of DGC.
We identified 20 carriers of germline CDH1 PLP variants; they underwent endoscopic examinations and/or gastrectomy. None had abnormal findings visible during endoscopy. Signet ring cell carcinoma (SRCC) was detected in 12 of 20 subjects. All but 1 of the carcinomas were tiny and confined to the lamina propria, and 1 was transmural. Seven of 12 subjects who had SRCC reported no diagnoses of DGC in first-degree relatives and did not meet established criteria for CDH1 analysis based on a 3-generation family pedigree.
More than half of individuals with germlines variants of CDH1 that are PLP had histopathologic evidence for DGC on endoscopy and/or gastrectomy. Family history of DGC and endoscopic findings therefore do not appear to be reliable determinants of risk of SRCC in individuals with genetic predisposition to DGC.
CDH1 种系致病性变异与弥漫性胃癌（DGC）和乳腺小叶癌的发病风险相关。鉴于 DGC 的高发病率和内镜检测的有限敏感性，对于携带 CDH1 致病性或可能致病性（PLP）种系变异的个体，建议行预防性全胃切除术。多基因panel 检测发现，越来越多的 CDH1 PLP 变异携带者无 DGC 家族史。本研究旨在评估有或无 DGC 家族史的 CDH1 PLP 变异携带者行内镜监测的结局。
1998 年 1 月至 2018 年 5 月，密歇根大学医学中心癌症遗传学诊所对 13 个携带有 CDH1 种系 PLP 变异的家族中的个体进行了评估。比较了有和无 DGC 家族史的个体行上消化道内镜检查、组织病理学分析和手术的结局。
我们共发现 20 例携带有 CDH1 种系 PLP 变异的个体；他们接受了内镜检查和/或胃切除术。内镜检查未见异常。20 例个体中，12 例检出印戒细胞癌（SRCC）。除 1 例外，所有的癌灶均很小且局限于固有层，其中 1 例为黏膜下浸润。12 例 SRCC 中有 7 例个体报告一级亲属中无 DGC 诊断，且基于 3 代家族系谱，不符合 CDH1 分析的既定标准。
超过一半携带有 CDH1 PLP 变异的个体，内镜检查和/或胃切除术后有 DGC 的组织病理学证据。因此，DGC 家族史和内镜检查结果似乎不能可靠地预测有 DGC 遗传易感性个体发生 SRCC 的风险。
