BACKGROUND & AIMS Lynch syndrome is the most common inherited cause of gastrointestinal cancer and increases risk for a variety of malignancies, including gastric cancer. We aimed to identify clinical factors associated with gastric cancer in carriers of germline variants causing Lynch syndrome. METHODS We collected data from 52,758 consecutive individuals tested for genetic variants associated with Lynch syndrome from June 2006 through July 2013 at a commercial laboratory. We obtained clinical and demographic data, as well as information on personal and family histories of cancer (first- and second-degree relatives) from forms completed by ordering providers. We performed multivariate logistic regression to identify clinical factors associated with gastric cancer in carriers of mutations that cause Lynch syndrome (pathogenic mutations). RESULTS After we excluded individuals with missing clinical data (n = 1664) or with multiple pathogenic mutations (n = 8), we analyzed data from 51,086 individuals. Of these, 3828 persons carried pathogenic mutations (1346 with mutations in MLH1, 1639 with mutations in MSH2, 670 with mutations in MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM). Of the 3828 carriers of pathogenic mutations, 41 (1.1%) had a previous gastric cancer and 350 (9.1%) had 1 or more first- or second-degree relatives with gastric cancer. In multivariate analysis, male sex (odds ratio [OR], 2.82; 95% CI, 1.48-5.38), older age (OR, 2.07 per 10 years; 95% CI, 1.64-2.61), mutations in MLH1 (OR, 6.53; 95% CI, 1.50-28.42) or MSH2 (OR, 5.23 compared to mutations in MSH6, PMS2, or EPCAM; 95% CI, 1.21-22.71), and number of first-degree relatives with gastric cancer (OR, 2.52; 95% CI, 1.42-4.45), but not second-degree relatives (OR, 1.12; 95% CI, 0.40-3.18) were independently associated with gastric cancer among carriers of pathogenic mutations. CONCLUSIONS In an analysis of data from almost 4000 carriers of Lynch syndrome-associated mutations, we found history of gastric cancer to be independently associated with male sex, older age, mutations in MLH1 or MSH2, and number of first-degree relatives with gastric cancer. These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome-associated mutations.

中文翻译：

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与林奇综合征患者胃癌相关的临床因素。

背景和目的 Lynch 综合征是胃肠道癌最常见的遗传原因，会增加多种恶性肿瘤（包括胃癌）的风险。我们的目的是在导致 Lynch 综合征的种系变异携带者中确定与胃癌相关的临床因素。方法 我们从 2006 年 6 月至 2013 年 7 月在商业实验室收集了 52,758 名连续测试与林奇综合征相关的遗传变异的个体的数据。我们从订购提供者填写的表格中获取了临床和人口统计数据，以及关于癌症个人和家族史（一级和二级亲属）的信息。我们进行了多变量逻辑回归，以确定导致 Lynch 综合征（致病性突变）突变携带者中与胃癌相关的临床因素。结果 在我们排除了临床数据缺失（n = 1664）或具有多个致病突变（n = 8）的个体后，我们分析了来自 51,086 个个体的数据。其中，3828人携带致病突变（1346人为MLH1突变，1639人为MSH2突变，670人为MSH6突变，145人为PMS2突变，28人为EPCAM突变）。在 3828 名致病突变携带者中，41 名（1.1%）既往患有胃癌，350 名（9.1%）有 1 个或多个一级或二级亲属患有胃癌。在多变量分析中，男性（优势比 [OR]，2.82；95% CI，1.48-5.38），年龄较大（OR，2.07 每 10 年；95% CI，1.64-2.61），MLH1 突变（OR，6.53 ; 95% CI, 1.50-28.42) 或 MSH2 (OR, 5.23 与 MSH6、PMS2 或 EPCAM 中的突变相比; 95% CI, 1.21-22.71), 和胃癌的一级亲属（OR，2.52；95% CI，1.42-4.45），但不是二级亲属（OR，1.12；95% CI，0.40-3.18）与胃癌独立相关致病突变的携带者。结论 在对近 4000 名 Lynch 综合征相关突变携带者的数据进行分析时，我们发现胃癌病史与男性、年龄较大、MLH1 或 MSH2 突变以及胃癌一级亲属数量独立相关。 . 这些发现表明，个性化、风险分层的胃癌监测方法可能适用于林奇综合征相关突变的个体。18) 在致病突变携带者中与胃癌独立相关。结论 在对近 4000 名 Lynch 综合征相关突变携带者的数据进行分析时，我们发现胃癌病史与男性、年龄较大、MLH1 或 MSH2 突变以及胃癌一级亲属数量独立相关。 . 这些发现表明，个性化、风险分层的胃癌监测方法可能适用于林奇综合征相关突变的个体。18) 在致病突变携带者中与胃癌独立相关。结论 在对近 4000 名 Lynch 综合征相关突变携带者的数据进行分析时，我们发现胃癌病史与男性、年龄较大、MLH1 或 MSH2 突变以及胃癌一级亲属数量独立相关。 . 这些发现表明，个性化、风险分层的胃癌监测方法可能适用于林奇综合征相关突变的个体。