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

• Published in: Genetics in medicine Vol. 22; no. 2; pp. 407 - 415
• Main Authors: LaDuca, Holly, Polley, Eric C, Yussuf, Amal, Hoang, Lily, Gutierrez, Stephanie, Hart, Steven N, Yadav, Siddhartha, Hu, Chunling, Na, Jie, Goldgar, David E, Fulk, Kelly, Smith, Laura Panos, Horton, Carolyn, Profato, Jessica, Pesaran, Tina, Gau, Chia-Ling, Pronold, Melissa, Davis, Brigette Tippin, Chao, Elizabeth C, Couch, Fergus J, Dolinsky, Jill S
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.02.2020; Nature Publishing Group US
• Subjects: Adult; Aged; Biomarkers, Tumor - genetics; BRCA1 Protein - genetics; Breast Neoplasms - genetics; Clinical medicine; Cohort Studies; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Female; Genes; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease - genetics; Genetic testing; Genetic Testing - methods; Genetics; Genomics; Germ-Line Mutation - genetics; Humans; Laboratories; Male; Medicine; Melanoma; Middle Aged; Mutation - genetics; Neoplasms - genetics; Ovarian cancer; Ovarian Neoplasms - genetics; multigene panel; testing criteria; cancer predisposition; hereditary cancer; clinical validity
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-019-0633-8

Despite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include. To 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. We 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. 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.