Kim Jaihwan, Braun Danielle, Ukaegbu Chinedu, Dhingra Tara G, Kastrinos Fay, Parmigiani Giovanni, Syngal Sapna, Yurgelun Matthew B
Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Clin Gastroenterol Hepatol. 2020 Apr;18(4):830-837.e1. doi: 10.1016/j.cgh.2019.07.012. Epub 2019 Jul 15.
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.
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).
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.
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.
林奇综合征是胃肠道癌最常见的遗传性病因，会增加包括胃癌在内的多种恶性肿瘤的发病风险。我们旨在确定导致林奇综合征的种系变异携带者中与胃癌相关的临床因素。
我们收集了2006年6月至2013年7月在一家商业实验室对52758名连续个体进行林奇综合征相关基因变异检测的数据。我们从订购机构填写的表格中获取了临床和人口统计学数据，以及个人和癌症家族史（一级和二级亲属）信息。我们进行多因素逻辑回归分析，以确定导致林奇综合征的突变（致病突变）携带者中与胃癌相关的临床因素。
在排除临床数据缺失的个体（n = 1664）或有多个致病突变的个体（n = 8）后，我们分析了51086名个体的数据。其中，3828人携带致病突变（1346人携带MLH1突变，1639人携带MSH2突变，670人携带MSH6突变，145人携带PMS2突变，28人携带EPCAM突变）。在3828名致病突变携带者中，41人（1.1%）曾患胃癌，350人（9.1%）有1名或更多一级或二级亲属患胃癌。在多因素分析中，男性（比值比[OR]，2.82；95%置信区间[CI]，1.48 - 5.38）、年龄较大（每10岁OR，2.07；95% CI，1.64 - 2.61）、MLH1（OR，6.53；95% CI，1.50 - 28.42）或MSH2突变（与MSH6、PMS2或EPCAM突变相比，OR，5.23；95% CI，1.21 - 22.71）以及患胃癌的一级亲属数量（OR，2.52；95% CI，1.42 - 4.45），但不包括二级亲属（OR，1.12；95% CI，0.40 - 3.18）在致病突变携带者中与胃癌独立相关。
在对近4000名林奇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突变以及患胃癌的一级亲属数量独立相关。这些发现表明，针对林奇综合征相关突变个体，采用个性化、风险分层的胃癌监测方法可能是合适的。
