Universal Germline Genetic Testing after a Diagnosis of Cancer

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.