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

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.

Keywords: cancer predisposition; clinical validity; hereditary cancer; multigene panel; testing criteria.

Fig. 1

Gene-specific cancer associations derived from panel cases vs. gnomAD non-Finnish European (NFE) reference controls. Gene-specific associations, along with corresponding 95% confidence intervals (CI), are shown for breast cancer (BC), colorectal cancer (CRC), melanoma (MEL), ovarian cancer (OC), pancreatic cancer (PC), and uterine/endometrial cancer (UEC). Case–control analysis was performed by pooling pathogenic variants (PVs) to the gene level and comparing the frequency in Caucasian multigene panel testing (MGPT) cases relative to NFE gnomAD controls. Genes with <5 PVs detected in cases and/or controls are not shown; however, complete analysis results are shown in Table S4.

Fig. 2

Pathogenic variant frequency by gene and clinical history. Pooled pathogenic variant frequencies (%) are shown across a range of phenotypic groups based on proband and family history of cancer. Genes were grouped as follows: BRCA1/2, other breast and/or ovarian cancer genes (ATM, CHEK2, PALB2, BARD1, BRIP1, RAD51C, RAD51D, NBN, TP53, CDH1, PTEN, NF1), Lynch syndrome genes (MLH1, EPCAM/MSH2, MSH6, PMS2), and other cancer predisposition genes (STK11, CDKN2A, CDK4, SMARCA4, APC, MUTYH, BMPR1A, SMAD4, GREM1, POLD1, POLE). Pooled pathogenic frequencies exclude patients with additional cancer types unless otherwise noted. With the exception of “BC <50 + additional primary BC”, pooled pathogenic frequencies are limited to females with a single primary breast cancer. BC breast cancer, CRC colorectal cancer, OC ovarian cancer, PC pancreatic cancer, TNBC triple negative breast cancer, UEC uterine/endometrial cancer.

Fig. 3

Distribution of pathogenic/likely pathogenic variants based on genetic testing criteria met. The distribution of pathogenic variants (PVs) based on genetic testing criteria met was assessed for patients tested for all 32 cancer predisposition genes (n = 33,987). Total PV counts among patients meeting only BRCA1/2 criteria, only Lynch criteria, both criteria, and neither criteria are shown in parenthesis. Genes were grouped as follows: BRCA1/2, other breast and/or ovarian cancer genes (ATM, CHEK2, PALB2, BARD1, BRIP1, RAD51C, RAD51D, NBN, TP53, CDH1, PTEN, NF1), Lynch syndrome genes (MLH1, EPCAM/MSH2, MSH6, PMS2), and other cancer predisposition genes (STK11, CDKN2A, CDK4, SMARCA4, APC, MUTYH, BMPR1A, SMAD4, GREM1, POLD1, POLE, MRE11A, RAD50).