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

MedStar author(s):
Citation: Journal of Medical Genetics. 56(6):370-379, 2019 06.PMID: 30745422Institution: MedStar Washington Hospital CenterDepartment: Surgery/General SurgeryForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Antigens, CD/ge [Genetics] | *Cadherins/ge [Genetics] | *Genetic Association Studies | *Genetic Predisposition to Disease | *Germ-Line Mutation | *Phenotype | *Stomach Neoplasms/di [Diagnosis] | *Stomach Neoplasms/ge [Genetics] | Alleles | Alternative Splicing | Antigens, CD/ch [Chemistry] | Antigens, CD/me [Metabolism] | Cadherins/ch [Chemistry] | Cadherins/me [Metabolism] | Exons | Family | Humans | Immunohistochemistry | Mutation, Missense | Odds Ratio | Pedigree | Signal Transduction | Stomach Neoplasms/me [Metabolism]Year: 2019Local holdings: Available online through MWHC library: 1964 - 2005ISSN:
  • 0022-2593
Name of journal: Journal of medical geneticsAbstract: CONCLUSION: 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.Copyright (c) Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.INTRODUCTION: 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.METHODS: 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).RESULTS: 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 beta-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants.All authors: Beane JD, Calzone K, Chen I, Heller T, Hewitt SM, Koh C, Lo W, McDuffie LA, Miettinen MM, Powers A, Quadri HS, Ravichandran S, Rudloff U, Sabesan A, Sorber RA, Wacholder S, Wu HH, Zhu BOriginally published: Journal of Medical Genetics. 2019 Feb 11Fiscal year: FY2019Digital Object Identifier: Date added to catalog: 2019-03-14
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 30745422 Available 30745422

Available online through MWHC library: 1964 - 2005

CONCLUSION: 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.

Copyright (c) Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

INTRODUCTION: 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.

METHODS: 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).

RESULTS: 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 beta-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants.

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