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

Germline pathogenic/likely pathogenic variants in predisposition genes, dominated by APC, MLH1, MSH2, MUTYH, BRCA2 and TP53.

The Jordanian Jo-ECAG programme offered multigene germline panel testing to 652 males aged 50 years or younger with a newly diagnosed solid tumour, irrespective of tumour type, stage or family history. Colorectal cancer predominated (48.0%), followed by gastric (6.7%), pancreatic (6.4%) and testicular (6.0%) cancers. Overall, 90 patients (13.8%) carried a pathogenic or likely pathogenic variant and 216 (33.1%) a variant of uncertain significance. Yield was higher in patients meeting NCCN criteria (16.5% vs 4.7%, p<0.001) and rose at younger ages (26.3% at 18-30 years vs 9.7% at 41-50 years, p<0.001). The most frequently altered genes were APC, MLH1, MSH2, MUTYH, BRCA2 and TP53, with no pathogenic BRCA1 variants identified.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The number that matters in clinic is the 4.7% yield in men not meeting NCCN criteria: low compared with eligible patients, yet high enough to make declining testing hard to justify for any solid tumour before age 50. The one-third rate of variants of uncertain significance is the real cost of this broad strategy and will have to be absorbed by interpretation work, not by widening the gene list further. The absence of BRCA1 variants and the colorectal predominance reflect single-referral-centre recruitment: this spectrum cannot be transposed as is to an unselected population.

Analysis by Dr Thibaut Benquey