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

Holly LaDuca, Eric C. Polley, Amal Yussuf, Lily Hoang, Stephanie Gutierrez, Steven N. Hart, Siddhartha Yadav, Chunling Hu, Jie Na, David E. Goldgar, Kelly Fulk, Laura Panos Smith, Carolyn Horton, Jessica Profato, Tina Pesaran, Chia Ling Gau, Melissa Pronold, Brigette Tippin Davis, Elizabeth C. Chao, Fergus J. CouchJill S. Dolinsky

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)407-415
Number of pages9
JournalGenetics in Medicine
Volume22
Issue number2
DOIs
StatePublished - Feb 1 2020

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Keywords

  • cancer predisposition
  • clinical validity
  • hereditary cancer
  • multigene panel
  • testing criteria

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

LaDuca, H., Polley, E. C., Yussuf, A., Hoang, L., Gutierrez, S., Hart, S. N., Yadav, S., Hu, C., Na, J., Goldgar, D. E., Fulk, K., Smith, L. P., Horton, C., Profato, J., Pesaran, T., Gau, C. L., Pronold, M., Davis, B. T., Chao, E. C., ... Dolinsky, J. S. (2020). 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. Genetics in Medicine, 22(2), 407-415. https://doi.org/10.1038/s41436-019-0633-8