A NEW study has identified pathogenic variants in WNT9B as significant risk factors for hereditary prostate cancer (HPC), shedding light on the genetic complexity underlying the disease.
The study employed genome-wide single-allele and identity-by-descent analyses to detect high-risk haplotypes, followed by sequencing for variant identification. Candidate variants were then tested across four independent biobanks to confirm their association with prostate cancer.
The WNT9B E152K variant conferred a 2.5-fold increased risk of prostate cancer, achieving genome-wide significance in a meta-analysis encompassing half a million patients. Another variant, WNT9B Q47R, was identified as a significant risk factor in Finnish populations, with identity-by-descent analysis confirming a founder effect.
Importantly, WNT9B was found to share a crucial developmental function with HOXB13 and HNF1B, two genes previously linked to prostate cancer risk. These genes are all required for embryonic prostate development, suggesting a potential mechanism by which early genitourinary development influences later cancer susceptibility. To explore this further, the study assessed KMT2D and DHCR7, genes known to cause Mendelian genitourinary developmental disorders, and found nominal associations with prostate cancer under meta-analysis.
These findings highlight a previously unrecognised genetic pathway linking early genitourinary development to prostate cancer risk. The identification of WNT9B as a hereditary prostate cancer gene could improve risk stratification and genetic screening, offering new avenues for early detection and targeted intervention in high-risk individuals.
Ada Enesco, EMJ
Reference
Dupont WD et al; VA Million Veteran Program. Coding variants of the genitourinary development gene WNT9B carry high risk for prostate cancer. JCO Precis Oncol. 2025; DOI:10.1200/PO-24-00569.
