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

Abstract

IntroductionHereditary 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.MethodsOne 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).ResultsFrequency 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.ConclusionType 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.

Role of endoscopy in the management of hereditary diffuse gastric cancer syndrome

“…Although the majority of research on HDGC has focused on the role of upper endoscopic examination, there is limited evidence that there may be an association of colorectal SRCC in patients with germline CDH1 pathogenic variants[1]. More recent work has also speculated that the CDH1 variant location may be an important predictor of colorectal cancer risk[37]. Although based on limited data, enhanced colorectal cancer screening by colonoscopy is recommended for CDH1 carriers with a family history of colon cancer, especially when there is a presence of signet ring cells and/or mucinous features of the cancer[1,17].…”

Frequency and Clinical Characteristics of Unselected Korean Gastric Cancer Patients with a Germline CDH1 V832M Mutation

“…Loss of function of E-cadherin impairs epithelial cell adhesiveness and contributes to cancer progression and metastasis 16. The germline pathogenic truncating and missense mutations are distributed throughout the entire CDH1 gene, and the V832M mutation is located in exon 16, the cytoplasmic domain of the protein 17. The V832M mutation was first identified in a Japanese HDGC family, and was reported again in a patient with early-onset lobular breast cancer 8,18.…”

“…CDH1 germline mutations have been described in about 40% of HDGC families and about 2.3% of sporadic early-onset gastric cancer patients 1. Recently, Lo et al 17 reported that the location and type of germline CDH1 variants are related to the age of cancer onset and risk of concomitant cancer in the HDGC families. However, data on the frequency and clinical characteristics of germline CDH1 mutations in unselected gastric cancer patients are scarce.…”

Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

“…Moreover, the absence of E-cadherin at the cellular surface may aid the malignant transformation of cells explaining the different cancer manifestations within the HDGC syndrome. An association between the status of CDH1 germline variants with the loss of the precursor region and clinical phenotypes of HDGC being more virulent has also been demonstrated [ 23 ]. Moreover, in families with truncating CDH1 germline variants affecting the precursor region, an increased probability of colorectal cancer has been evidenced [ 23 ].…”

“…An association between the status of CDH1 germline variants with the loss of the precursor region and clinical phenotypes of HDGC being more virulent has also been demonstrated [ 23 ]. Moreover, in families with truncating CDH1 germline variants affecting the precursor region, an increased probability of colorectal cancer has been evidenced [ 23 ]. In CDH1 germline mutation carriers, the possible explanation for the different intracellular transduction perturbations and variable cancer phenotypes might be the different levels of intracellular signal activation including different p-ERK, p-mTOR, and β-catenin levels or the differences in the truncating CDH1 variants to subject CDH1 mRNA transcripts to nonsense-mediated mRNA decay (NMD) [ 24 , 25 ].…”