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Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer

Dana Farengo Clark1, Scott T Michalski2, Rashmi Tondon3

  • 1Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|February 14, 2020
PubMed
Abstract

Insights

Cadherin-1 (CTNNA1) loss-of-function variants are found in multigene panel testing, often in patients with gastric or breast cancer. The gastric cancer risk for these carriers may be lower than anticipated.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • The gene CTNNA1 encodes α-E-catenin, a protein crucial for cell adhesion.
  • CTNNA1 is implicated as a potential risk gene for diffuse gastric cancer.
  • The prevalence and clinical significance of CTNNA1 variants in multigene panel testing (MGPT) are not well understood.

Purpose of the Study:

  • To investigate the occurrence and clinical implications of CTNNA1 variants identified through MGPT.
  • To assess the association between CTNNA1 loss-of-function (LOF) variants and gastric and breast cancer diagnoses.
  • To evaluate α-E-catenin expression in gastric cancers with CTNNA1 variants.

Main Methods:

  • Retrospective review of de-identified data from 151,425 individuals undergoing CTNNA1 testing.
  • Analysis of CTNNA1 variants, including LOF and missense variants of uncertain significance.
  • Immunohistochemistry for α-E-catenin in tissue from CTNNA1 c.1351C>T (p.Arg451*) carriers with gastric cancer.

Main Results:

  • CTNNA1 LOF variants were identified in 0.03% of individuals tested.
  • Of 33 CTNNA1 LOF carriers with detailed history, 12% had diffuse gastric cancer and 67% had breast cancer.
  • Immunohistochemistry revealed decreased α-E-catenin expression in gastric cancers from affected individuals.

Conclusions:

  • CTNNA1 LOF variants are detected via MGPT, frequently in individuals with a history of gastric or breast cancer.
  • The actual risk of gastric cancer associated with CTNNA1 LOF variants may be lower than previously suggested.
  • The management of individuals with CTNNA1 LOF variants presents challenges due to uncertain phenotype and penetrance.
Keywords:
CTNNA1breast cancercancer risk assessmentdiffuse gastric cancermultigene panel testing

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