Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges
Katrina Lowstuter1, Carin R Espenschied1, Duveen Sturgeon1
1Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA.
Genetic testing for CDH1 mutations often identifies carriers who don't meet standard criteria. This finding impacts cancer risk management and early detection strategies for families.
Area of Science:
- Genetics
- Oncology
- Cancer Predisposition Syndromes
Background:
- CDH1 gene mutations significantly increase lifetime risks for diffuse gastric cancer (up to 80%) and lobular breast cancer (up to 60%).
- Current guidelines, such as the International Gastric Cancer Linkage Consortium (IGCLC), recommend CDH1 mutation testing for specific high-risk individuals.
- Interpreting unexpected CDH1 mutations in patients outside IGCLC criteria presents clinical challenges.
Purpose of the Study:
- To describe the clinical phenotypes of individuals carrying CDH1 mutations identified through multigene panel testing (MGPT).
- To provide evidence-based recommendations for the medical management of CDH1 mutation carriers.
- To assess the prevalence of CDH1 mutations in broader patient populations undergoing genetic testing.
Main Methods:
- A cross-sectional prevalence study analyzed data from 26,936 patients from a commercial laboratory and 318 from an academic medical center.
- Patients undergoing MGPT between March 2012 and September 2014 were included.
- CDH1 mutation carriers were categorized based on adherence to IGCLC criteria: IGCLC positive, IGCLC partial phenotype, and IGCLC negative.
Main Results:
- Pathogenic CDH1 mutations were found in 0.06% of the commercial laboratory cohort and 1.26% of the academic clinic cohort.
- A significant proportion, 65% of identified CDH1 mutation carriers, did not meet the established IGCLC testing criteria.
- Three carriers who underwent risk-reducing gastrectomy showed pathological evidence of diffuse gastric cancer, despite not meeting IGCLC criteria.
Conclusions:
- The majority of CDH1 mutations detected via MGPT are unexpected, occurring in individuals not meeting current diagnostic testing guidelines.
- These findings necessitate adjustments in medical management for CDH1-positive individuals and their families.
- Early detection and risk reduction opportunities are enhanced by identifying mutations in broader patient groups.
