Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA.
J Med Genet. 2019 Jun;56(6):370-379. doi: 10.1136/jmedgenet-2018-105361. Epub 2019 Feb 11.
Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC.
One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age).
Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants.
Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.
遗传性弥漫性胃癌（HDGC）是一种与 E-钙黏蛋白（CDH1）、弥漫性胃癌和乳腺小叶癌变异相关的癌症综合征。其临床表现存在相当大的异质性。本研究旨在确定 CDH1 种系变异状态与 HDGC 的临床表型之间的关联。
鉴定了 152 个 HDGC 家族，包括 6 个以前未报道的家族。应用临床基因组资源（ClinGen）CDH1 变异管理专家小组发布的 CDH1 基因特异性指南，对截断、错义及剪接位点 CDH1 种系变异进行致病性分类。我们评估了 CDH1 截断变异的位置与结直肠癌、乳腺癌和年轻发病（<40 岁的胃癌或<50 岁的乳腺癌）之间的 OR 值。
E-钙黏蛋白受体基因功能域中截断种系 CDH1 变异的频率不同，在连接区（0.05785 个计数/碱基对；p=0.0111）和 PRE 区（0.10000；p=0.0059）最高。具有 PRE-PRO 区截断 CDH1 种系变异的家族中，结直肠癌受累家庭成员的可能性是其他区域种系变异的六倍（OR 6.20，95%CI 1.79 至 21.48；p=0.004）。细胞内 E-钙黏蛋白区的变异对年轻发病的癌症具有保护作用（OR 0.2，95%CI 0.06 至 0.64；p=0.0071），而连接区的变异对乳腺癌具有保护作用（OR 0.35，95%CI 0.12 至 0.99；p=0.0493）。不同的 CDH1 基因型与不同的细胞内信号激活水平相关，包括不同 CDH1 变异的 HDGC 家族中早期黏膜下 T1a 病变中的不同 p-ERK、p-mTOR 和 β-连环蛋白水平。
CDH1 种系变异的类型和位置可能有助于识别伴有癌症风险增加的家族，这些家族可能受益于个体化监测和干预策略。
