Coding Variants of the Genitourinary Development Gene WNT9B Carry High Risk for Prostate Cancer

Considerable genetic heterogeneity is currently thought to underlie hereditary prostate cancer (HPC). Most families meeting criteria for HPC cannot be attributed to currently known pathogenic variants.

To discover pathogenic variants predisposing to prostate cancer, we conducted a familial case-control association study using both genome-wide single-allele and identity-by-descent analytic approaches. Sequence of high-risk haplotype carriers was used for variant detection. Candidate pathogenic variants were tested for association with prostate cancer across independent biobanks for replication of observations.

Pathogenic variants within WNT9B were associated with familial prostate cancer and observations replicated within four of four independent biobanks. WNT9B E152K carried 2.5-fold risk and reached genome-wide significance under meta-analysis, collectively encompassing a half million patients. WNT9B Q47R was also associated with prostate cancer with genome-wide significance among Finns, for which identity-by-descent analyses confirmed a founder effect. WNT9B shares an unexpected commonality with the previously established prostate cancer risk genes HOXB13 and HNF1B: they are each required for embryonic prostate development. With this recognition, we further evaluated two additional genes known to cause Mendelian genitourinary developmental defects, KMT2D and DHCR7. These too were nominally associated with prostate cancer under meta-analyses.

WNT9B and additional genes that are required for early genitourinary development are also involved in the later development of prostate cancer.