Universal Germline Genetic Testing after a Diagnosis of Cancer

Age at diagnosis among patients with cancer is a predictor of pathogenic germline variant prevalence, yet age thresholds often misclassify genetic risk. We performed germline sequencing of 39,184 unselected patients with solid malignancies spanning 32 tumor types, interrogating >90 cancer predisposition genes independent of clinical suspicion. Patients were stratified into early-, average-, and late-onset groups based on standard deviations from tumor-specific mean age at diagnosis. Pathogenic variant prevalence inversely correlated with age at diagnosis: 18.4% in early-onset tumors, 15.6% in average-onset tumors, and 12.3% in late-onset tumors (P < 0.001). Variants in high/moderate-penetrance genes accounted for the enrichment in early-onset cases (12.4%, early-onset; 8.9%, average-onset; 5.1%, late-onset; P < 0.001). Restricting hereditary cancer testing to patients diagnosed before age 50, as is typically done, would miss 4,601 pathogenic variant carriers, 72% of all variants detected. These findings support broad-based germline testing beyond conventional age-based criteria, reflecting the burden of hereditary risk even among late-onset cases. SIGNIFICANCE: Across 32 solid tumor types in a pan-cancer cohort, we found enrichment of germline pathogenic variants among patients with subtype-specific early-onset cancer. Using age 50 as a testing cutoff misses most patients with inherited predisposition, supporting universal germline genetic testing for all individuals diagnosed with cancer.

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Publication Details

Journal
Cancer Discovery
Published
2026-10-08
DOI
https://doi.org/10.1158/2159-8290.cd-26-0971
Primary Topic
BRCA gene mutations in cancer
Type
article
Field-Weighted Citation Impact
0.00
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article

Universal Germline Genetic Testing after a Diagnosis of Cancer

Kenneth Offit, Lisa Marie DeAngelis, Michael David Offin, Ozge Ceyhan‐Birsoy et al.
Cancer Discovery
BRCA gene mutations in cancer
article

Universal Germline Genetic Testing after a Diagnosis of Cancer

Kenneth Offit, Lisa Marie DeAngelis, Michael David Offin, Ozge Ceyhan‐Birsoy, Kanika S. Arora, Erin E. Salo‐Mullen, Ingo K. Mellinghoff, Lauren Gabriele Banaszak, William D. Tap, Andrea Cercek, Yonina R. Murciano‐Goroff, Alan Loh Ho, Michael F. Berger, Yelena M. Kemel, Alexander Noor Shoushtari, Tina Alano, Mark E. Robson, Marc Ladanyi, Luis Alberto Diaz, Ying L. Liu, Mohammad Ali Abbass, Diana L. Mandelker, Anna Maio, Maria Isabel Carlo, Zsofia Kinga Stadler, Chimene A. Kesserwan, Eileen Mary O'Reilly, Margaret R. Sheehan, Alicia J. Latham, Angelika Padunan, Aliya Khurram, Julia Glade Bender, Chaitanya Bandlamudi, David B. Solit
article en

Abstract

Age at diagnosis among patients with cancer is a predictor of pathogenic germline variant prevalence, yet age thresholds often misclassify genetic risk. We performed germline sequencing of 39,184 unselected patients with solid malignancies spanning 32 tumor types, interrogating >90 cancer predisposition genes independent of clinical suspicion. Patients were stratified into early-, average-, and late-onset groups based on standard deviations from tumor-specific mean age at diagnosis. Pathogenic variant prevalence inversely correlated with age at diagnosis: 18.4% in early-onset tumors, 15.6% in average-onset tumors, and 12.3% in late-onset tumors (P < 0.001). Variants in high/moderate-penetrance genes accounted for the enrichment in early-onset cases (12.4%, early-onset; 8.9%, average-onset; 5.1%, late-onset; P < 0.001). Restricting hereditary cancer testing to patients diagnosed before age 50, as is typically done, would miss 4,601 pathogenic variant carriers, 72% of all variants detected. These findings support broad-based germline testing beyond conventional age-based criteria, reflecting the burden of hereditary risk even among late-onset cases. SIGNIFICANCE: Across 32 solid tumor types in a pan-cancer cohort, we found enrichment of germline pathogenic variants among patients with subtype-specific early-onset cancer. Using age 50 as a testing cutoff misses most patients with inherited predisposition, supporting universal germline genetic testing for all individuals diagnosed with cancer.

Cancer Discovery
Memorial Sloan Kettering Cancer Center (US)
Openalex Percentile: Top 14%
BRCA gene mutations in cancer
DOISourceOpenAlex
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