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.
Highlights
Identification of patients at risk for inherited cancer susceptibility is dependent upon the ability to characterize genes and alterations associated with increased cancer risk and establish appropriate indications for genetic testing
Opportunities 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
Genetic testing guidelines have evolved over the past few years to incorporate genes included on multigene panel testing (MGPT) for hereditary cancer into clinical practice
Summary
Identification of patients at risk for inherited cancer susceptibility is dependent upon the ability to characterize genes and alterations associated with increased cancer risk and establish appropriate indications for genetic testing. With the exponential uptake of next-generation sequencing–based hereditary cancer panels, the curation and analysis of large data sets have furthered our understanding of a full spectrum of clinically relevant cancer predisposition genes. Genetic testing guidelines have evolved over the past few years to incorporate genes included on multigene panel testing (MGPT) for hereditary cancer into clinical practice. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian[14] and NCCN Guidelines® for Genetic/Familial High-Risk Assessment: Colorectal[15] provide some information surrounding cancer risks and management recommendations for a range of genes included on multigene panel tests.
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