Dataset Information

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer.

ABSTRACT: The reported penetrance of germline CDH1 mutations is high in families with hereditary diffuse gastric cancer (HDGC). Men and women have a 70% and 56%, respectively, cumulative risk of developing diffuse gastric cancer by age 80. Women additionally have a 42% cumulative risk of developing breast cancer. Due to the high penetrance of these mutations, prophylactic total gastrectomy is currently recommended for CDH1 mutation carriers. However, whether everyone with a CDH1 gene mutation is at risk for HDGC is not clear.Mutation identification was performed by next-generation sequencing. Mutations and variant status was confirmed by Sanger sequencing in 11 family members.We present two families with pathogenic CDH1 mutations. The first family carries a novel truncating, nonsense CDH1 mutation that we were able to trace for three generations, but reports no family history of diffuse gastric cancer. The occurrence of cancer in this family deviates significantly from the expectation for HDGC. The proband from the second family presents with breast cancer and carries a previously reported pathogenic CDH1 mutation, but also reports no family history of diffuse gastric cancer.Our study demonstrates the need for further analysis of CDH1 mutation penetrance in order to better counsel asymptomatic CDH1 mutation carriers on preventative measures and general care.

SUBMITTER: Huynh JM

PROVIDER: S-EPMC4799867 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer.

Huynh Julie M JM Laukaitis Christina M CM

Molecular genetics & genomic medicine 20160113 2

<h4>Background</h4>The reported penetrance of germline CDH1 mutations is high in families with hereditary diffuse gastric cancer (HDGC). Men and women have a 70% and 56%, respectively, cumulative risk of developing diffuse gastric cancer by age 80. Women additionally have a 42% cumulative risk of developing breast cancer. Due to the high penetrance of these mutations, prophylactic total gastrectomy is currently recommended for CDH1 mutation carriers. However, whether everyone with a CDH1 gene mu ...[more]

PMID: 27064202

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Project description: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 ?-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. 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.

Project description:BackgroundGermline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants.MethodsWe did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer.FindingsProtein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant.InterpretationThe results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families.FundingUK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007-13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

Dataset Information

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer.

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Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer.

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