Roberts Maegan E, Ranola John Michael O, Marshall Megan L, Susswein Lisa R, Graceffo Sara, Bohnert Kelsey, Tsai Ginger, Klein Rachel T, Hruska Kathleen S, Shirts Brian H
GeneDx, Gaithersburg, Maryland.
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
JAMA Oncol. 2019 Sep 1;5(9):1325-1331. doi: 10.1001/jamaoncol.2019.1208.
CDH1 pathogenic variants have been estimated to confer a 40% to 70% and 56% to 83% lifetime risk for gastric cancer in men and women, respectively. These are likely to be overestimates owing to ascertainment of families with multiple cases of gastric cancer. To our knowledge, there are no penetrance estimates for CDH1 without this ascertainment bias.
To estimate CDH1 penetrance in a patient cohort not exclusively ascertained based on strict hereditary diffuse gastric cancer (HDGC) criteria.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 75 families found to have pathogenic variants in CDH1 through clinical ascertainment and multigene panel testing at a large commercial diagnostic laboratory from August 5, 2013, to June 30, 2018. CDH1 pathogenic variants were identified in 238 individuals from 75 families. Pedigrees from those families included cancer status for 1679 relatives. Penetrance estimates are based on 41 families for which completed pedigrees were available.
Gastric cancer standardized incidence ratio estimates relative to Surveillance, Epidemiology, and End Results (SEER) Program incidence for pathogenic CDH1 variants from families ascertained without regard to HDGC criteria.
Among the 238 individuals with a CDH1 pathogenic variant, mean (SD) age was 49.3 (18.1) years and 63.4% were female. Ethnicity was reported for 67 of 75 (89%) families; of these 67 families, 51 (76%) reported European ancestry, whereas Asian, African, Latino, and 2 or more ancestries were reported for 4 families (6%) each. Standardized incidence ratios for gastric and breast cancer were significantly elevated above SEER incidence. Extrapolated cumulative incidence of gastric cancer at age 80 years was 42% (95% CI, 30%-56%) for men and 33% (95% CI, 21%-43%) for women with pathogenic variants in CDH1, whereas cumulative incidence of female breast cancer was estimated at 55% (95% CI, 39%-68%). International Gastric Cancer Linkage Consortium criteria were met in 25 of the 75 (33%) families; however, dispensing with the requirement of confirmation of HDGC histologic subtype, 43 (57%) would meet criteria.
The cumulative incidence of gastric cancer for individuals with pathogenic variants in CDH1 is significantly lower than previously described. Because prophylactic gastrectomy can have bearing upon both physical and psychological health, further discussion is warranted to assess whether this surgical recommendation is appropriate for all individuals with pathogenic variants in CDH1.
据估计，CDH1致病变异分别使男性和女性患胃癌的终生风险达到40%至70%以及56%至83%。由于对有多例胃癌病例的家庭进行了确诊，这些估计值可能存在高估。据我们所知，在没有这种确诊偏倚的情况下，尚无CDH1外显率的估计值。
在一个并非完全根据严格的遗传性弥漫性胃癌（HDGC）标准确诊的患者队列中估计CDH1外显率。
设计、设置和参与者：对2013年8月5日至2018年6月30日期间在一家大型商业诊断实验室通过临床确诊和多基因检测发现有CDH1致病变异的75个家庭进行回顾性研究。在75个家庭的238名个体中鉴定出CDH1致病变异。这些家庭的系谱包括1679名亲属的癌症状况。外显率估计基于41个有完整系谱的家庭。
相对于监测、流行病学和最终结果（SEER）计划发病率，对未按照HDGC标准确诊的家庭中致病性CDH1变异的胃癌标准化发病率进行估计。
在238名携带CDH1致病变异的个体中，平均（标准差）年龄为49.3（18.1）岁，63.4%为女性。75个家庭中有67个（89%）报告了种族；在这67个家庭中，51个（76%）报告有欧洲血统，4个家庭（6%）分别报告有亚洲、非洲、拉丁裔血统以及两种或更多血统。胃癌和乳腺癌的标准化发病率显著高于SEER发病率。携带CDH1致病变异的男性在80岁时的外推胃癌累积发病率为42%（95%CI，30% - 56%），女性为33%（95%CI，21% - 43%），而女性乳腺癌的累积发病率估计为55%（95%CI，39% - 68%）。75个家庭中有25个（33%）符合国际胃癌连锁联盟标准；然而，若不要求确认HDGC组织学亚型，则43个（57%）家庭将符合标准。
携带CDH1致病变异个体的胃癌累积发病率显著低于先前描述的水平。由于预防性胃切除术会对身心健康产生影响，因此有必要进一步讨论评估该手术建议是否适用于所有携带CDH1致病变异的个体。
