Importance Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer.

Objective To assess gastric cancer risk among patients who received a diagnosis of hereditary lobular breast cancer (HLBC) owing to a germline loss-of-function variant in CDH1 by establishing prevalence of signet ring cell carcinomas among asymptomatic patients.

Design, Setting, and Participants A prospective cohort study of patients with germline CDH1 pathogenic or likely pathogenic (P/LP) variants at a quaternary medical center were enrolled between October 2017 and January 2021. Data analysis was performed in May 2021. Analyses for associations were performed for these 3 patient groups: (1) family history of breast cancer and no gastric cancer in the HLBC group; (2) family history of gastric cancer and no breast cancer in the hereditary diffuse gastric cancer (HDGC) group; and (3) family history of both breast and gastric cancers in the mixed group. Categorical variables were compared using the Pearson χ² test.

Main Outcomes and Measures The primary end point of this study was the prevalence of occult signet ring cell carcinoma of the stomach in patients with HLBC. Personal and family medical history, genotype, and pathologic data from risk-reducing total gastrectomy and surveillance endoscopy were examined.

Results A total of 283 patients with CDH1 P/LP variants (199 [70.3%] were female, and 259 [91.5%] were White; median age, 48 years [range, 18-81 years]) were enrolled in a prospective study of HDGC. The cohort consisted of 151 families. Patients were categorized according to family history of breast and/or gastric cancer: HLBC 15.5% [44 of 283 patients]), HDGC (16.2% [46 of 283 patients]), and mixed (68.2% [193 of 283 patients]). The HLBC group included 31 distinct families with 19 CDH1 variants; 10 of those variants were also present in the HDGC and mixed groups (52.6% [10 of 19 variants]). Nearly all of the patients with HLBC (93.8% [15 of 16 variants]) who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology (median age, 50 years [range, 21-67 years]). The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similar (94.7% [18 of 19 of variants]; P = .98).

Conclusions and Relevance Carriers of CDH1 P/LP variants with no family history of gastric cancer exhibited high rates of occult signet ring cell gastric cancer. Germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history. These data may prove useful for counseling families with CDH1 variants presumed to have HLBC.

重要性 生殖系基因变异的存在比癌症家族史更能说明遗传性癌症风险。

目的 通过确定无症状患者印戒细胞癌的患病率，评估因CDH1种系功能丧失变异体而被诊断为遗传性小叶乳腺癌 (HLBC) 的患者的胃癌风险。

设计、设置和参与者2017 年 10 月至 2021 年 1 月期间，在四级医疗中心对具有生殖系 CDH1致病性或可能致病性 (P/LP) 变异的患者进行了前瞻性队列研究。数据分析于 2021 年 5 月进行。关联分析对这3组患者进行了检查：（1）HLBC组有乳腺癌家族史且无胃癌；（2）遗传性弥漫性胃癌（HDGC）组有胃癌家族史且无乳腺癌；(3)混合组有乳腺癌和胃癌家族史。使用 Pearson χ ²检验比较分类变量。

主要结果和措施 本研究的主要终点是 HLBC 患者胃部隐匿印戒细胞癌的患病率。对来自降低风险的全胃切除术和监测内窥镜检查的个人和家族病史、基因型和病理学数据进行了检查。

结果 共有 283 名CDH1 P/LP 变异患者（199 名 [70.3%] 为女性，259 名 [91.5%] 为白人；中位年龄，48 岁 [范围，18-81 岁]）被纳入一项前瞻性研究HDGC 的。该队列由 151 个家庭组成。根据乳腺癌和/或胃癌家族史对患者进行分类：HLBC 15.5% [283 名患者中的 44 名]）、HDGC（16.2% [283 名患者中的 46 名]）和混合型（68.2% [283 名患者中的 193 名]） . HLBC 组包括 31 个具有 19 个CDH1变体的不同家族；其中 10 个变体也存在于 HDGC 和混合组中（52.6% [19 个变体中的 10 个]）。几乎所有 HLBC 患者（93.8% [16 种变体中的 15 种]）因其潜在的CDH1而选择降低风险的全胃切除术P/LP 变异体在最终病理上具有隐匿性印戒细胞胃腺癌（中位年龄，50 岁 [范围，21-67 岁]）。HDGC 组无症状患者的隐匿性胃癌患病率相似（94.7% [19 个变异中的 18 个]；P  = .98）。

结论和相关性无胃癌家族史的 CDH1 P/LP 变异携带者表现出较高的隐匿印戒细胞胃癌发生率。生殖系CDH1 P/LP 变体似乎具有高度渗透性的胃表型，与家族史无关。这些数据可能对咨询推测患有 HLBC的CDH1变异的家庭很有用。