Landscape of germline genetic alterations among non-western young male patients with cancer. Findings from The Jordanian exploratory cancer genetics study.

Early-onset cancers in males may indicate hereditary predisposition, yet real-world data on germline testing across diverse tumor types are limited. We evaluated the prevalence and spectrum of germline pathogenic/likely pathogenic (P/LP) variants in males diagnosed with cancer at ≤50 years. Consecutive male patients aged ≤50 years with newly diagnosed solid tumors enrolled in the Jordanian Exploratory Cancer Genetics (Jo-ECAG) program at the King Hussein Cancer Center underwent multigene panel germline testing irrespective of cancer type, stage, or family history. Patients were classified according to National Comprehensive Cancer Network (NCCN) testing criteria. P/LP and variant of uncertain significance (VUS) rates were analyzed by age, cancer type, and eligibility status. Among 652 patients (median age, 42 years), colorectal cancer predominated (48.0%), followed by gastric (6.7%), pancreatic (6.4%), and testicular (6.0%) cancers. Overall, 90 patients (13.8%) harbored P/LP variants and 216 (33.1%) had VUS. P/LP detection was higher among patients meeting NCCN criteria compared with those who did not (16.5% vs. 4.7%, p<0.001). Younger age was associated with higher yield (26.3% in ages 18-30 vs. 9.7% in 41-50 years, p<0.001). Colorectal cancer accounted for most pathogenic findings. Frequently altered genes included APC, MLH1, MSH2, MUTYH, BRCA2, and TP53; no BRCA1 P/LP variants were identified. Germline P/LP variants are common in young male patients with cancer, particularly at younger ages and among those meeting testing criteria. These findings support broader implementation of germline testing to inform management and familial risk assessment.