A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients |
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| Institution: | 1. Ambry Genetics, Aliso Viejo, CA, USA;;2. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;;3. Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA;;4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;;5. Department of Dermatology, University of Utah, Salt Lake City, UT, USA;;6. Department of Pediatrics, Division of Genetic and Genomic Medicine, University of California–Irvine, Irvine, CA, USA;1. Ambry Genetics, Aliso Viejo, CA, USA;;2. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;;3. Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA;;4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;;5. Department of Dermatology, University of Utah, Salt Lake City, UT, USA;;6. Department of Pediatrics, Division of Genetic and Genomic Medicine, University of California–Irvine, Irvine, CA, USA |
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| Abstract: | PurposeDespite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include.MethodsTo inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT.ResultsWe identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria.ConclusionOpportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers. |
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