2349P Patterns and frequency of pathogenic germline variants (PGVs) among non-western young male patients with cancer: The Jordanian exploratory cancer genetics (Jo-ECAG) study

Hereditary cancers have been less well-studied in men, particularly younger ones. The incidence of certain cancers associated with pathogenic germline variants (PGVs), such as breast and prostate, is low among men under the age of 50, while the incidence of other cancers, such as colorectal, is increasing. This study describes patterns and frequency of PGVs in a cohort of young men diagnosed with cancer. Male patients aged 50 years or younger, with newly diagnosed solid tumors were included in this prospective study. Patients were classified as in-criteria (IC) or out-of-criteria (OOC) based on the National Comprehensive Cancer Network (NCCN) v.1.2020 guidelines. All patients underwent an 84-gene panel test at a reference lab. Patients with one PGV in a gene associated with autosomal recessive inheritance (carriers), were excluded from analysis. A total of 397 male patients, mean (range) age at diagnosis 41 (18-50) years, were tested; 48 (12.1%) were 30 years or younger. Family history of any cancer was reported by 315 (79.3%). The most common primary tumor diagnoses were colorectal (n=157, 39.5%), testicular (n=38, 9.6%), pancreatic (n=26, 6.5%), lung (n=26, 6.5%), and sarcoma (n=22, 5.5%). In total, 246 (62.0%) were IC while the other 151 (38.0%) were OOC. PGVs were identified in 48 (19.5%) and 18 (11.9%) patients in IC and OOC groups, respectively, p<0.001. PGV rates were highest among patients with colorectal (23.6%) and pancreatic cancers (15.4%). PGV rates were significantly higher among patients <30 years (22.9%) compared to patients aged 41-50 years (13.4%), p=0.048. The majority of PGVs were actionable (therapeutic targets, clinical trials, and/or clinical management guidelines), with the most frequently affected genes were APC (n=11), MLH1 (n=11), BRCA2 (n=6), TP53 (n=5) and MSH2 (n=4). A significant number of males were diagnosed with cancer at young ages, especially colorectal or pancreatic cancer, with strikingly high PGV rates. Comprehensive genetic testing and counseling for this group of patients is critical to inform treatment options, risks of future cancers, and cascade testing.