Unexpected <i>CDH1</i> Mutations Identified on Multigene Panels Pose Clinical Management Challenges.

Abstract

Mutations in the <i>CDH1</i> gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for <i>CDH1</i> mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected <i>CDH1</i> mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of <i>CDH1</i> mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management. This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate <i>CDH1</i> mutation prevalence and associated clinical phenotypes. <i>CDH1</i> mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative. In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic <i>CDH1</i> mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic <i>CDH1</i> mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three <i>CDH1</i> mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria. The majority of <i>CDH1</i> mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of <i>CDH1</i>-positive patients and families and provide opportunities for early detection and risk reduction.