Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC)

Introduction Hereditary diffuse gastric cancer(HDGC) is a cancer syndromeassociated 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 germlinevariant status and clinical phenotypes of HDGC. Methods One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germlinevariants. We evaluated ORs between location of truncating variants of CDH1and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at Results Frequency of truncating germline CDH1variants 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 germlinevariants 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 germlinevariants 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 CDH1genotypes 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 CDH1variants. Conclusion Type and location of CDH1 germlinevariants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.