Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
JAMA. 2024 Sep 3;332(9):722-729. doi: 10.1001/jama.2024.10852.
Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants.
To describe gastric and breast cancer risk estimates for individuals with CDH1 variants.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022.
Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years.
A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%).
Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.
大约 1%至 3%的胃癌和 5%的乳腺小叶癌是遗传性的。功能丧失 CDH1 基因突变是与遗传性弥漫性胃癌和乳腺小叶癌最相关的基因突变。此前，有功能丧失 CDH1 基因突变的个体患胃癌的终生风险估计约为 25%至 83%，患乳腺癌的终生风险估计约为 39%至 55%。
描述携带 CDH1 变异体的个体的胃癌和乳腺癌风险估计。
设计、地点和参与者：这项多中心、回顾性队列和建模研究纳入了 2021 年 1 月至 2022 年 8 月期间北美 213 个家族的 213 名成员，这些家族中有 1 名或多名家庭成员携带 CDH1 致病性或可能致病性（P/LP）变异体。
风险比（HR）定义为变异携带者相对于非携带者的风险，用于估计每种癌症类型的风险，并计算累积风险和至 80 岁时每十年的风险。
共纳入 213 个家族的 7323 名个体，包括 883 名携带 CDH1 P/LP 变异体（中位先证者年龄，53 岁[四分位距，42-62]；4%为亚洲人；4%为西班牙裔；85%为非西班牙裔白人；50%为女性）。在携带 CDH1 P/LP 变异体的个体中，胃癌的患病率为 13.9%（123/883），女性携带者中乳腺癌的患病率为 26.3%（144/547）。30 岁时，进展期胃癌的估计 HR 为 33.5（95%CI，9.8-112），70 岁时为 3.5（95%CI，0.4-30.3）。男性和女性携带者终身患进展期胃癌的累积风险分别为 10.3%（95%CI，6%-23.6%）和 6.5%（95%CI，3.8%-15.1%）。基于家族史的胃癌风险估计表明，有 3 名一级亲属受影响的携带者的外显率约为 38%（95%CI，25%-64%）。女性携带者乳腺癌的 HR 为 30 岁时 5.7（95%CI，2.5-13.2）和 70 岁时 3.9（95%CI，1.1-13.7）。女性携带者乳腺癌的终身累积风险为 36.8%（95%CI，25.7%-62.9%）。
在携带胚系 CDH1 P/LP 变异体的北美家族中，胃癌的累积风险为 7%至 10%，低于此前的描述，女性携带者乳腺癌的累积风险为 37%，与此前的估计相似。这些发现为携带胚系 CDH1 变异体的个体的当前管理提供了信息。
