Pathogenic variants of WNT9B gene linked to hereditary prostate cancer

Pathogenic variants of the WNT9B gene and other genes needed for genitourinary development were associated with an increased risk of prostate cancer among men with a family history of the disease, according to findings from a recent study published in JCO Precision Oncology.¹

Jeffrey R. Smith, MD, PhD

“Unlike breast cancer, relatively few high-risk prostate cancer genes have been established to date,” explained senior author Jeffrey R. Smith, MD, PhD, in a news release on the findings.² “Inherited risk of prostate cancer is roughly twice that of breast cancer, but its genetic complexity is also considerably greater; this has been a formidable obstacle for global studies.”

For the current study, the investigators assessed the link between WNT9B gene mutations and risk of prostate cancer across 4 independent biobanks. Associations were uncovered using a case-control comparative design and genome-wide single-allele and identity by descent analytic approaches. 

Overall, data showed that the link between WNT9B gene mutations and prostate cancer was consistently replicated in each population. Specifically, WNT9B was associated with a 2- to 12-fold increase in the risk of prostate cancer across all 4 studies.

The investigators also assessed specific variants. One variant, WNT9B E152K, led to a 2.5-fold increase in the risk of prostate cancer, which “reached genome-wide significance under meta-analysis, collectively encompassing a half million patients,” according to the authors.

An additional variant, WNT9B Q47R, was also shown to increase the risk of familial prostate cancer in a Finnish population. An identify-by-descent analysis of this biobank confirmed a founder effect.

With these findings, WNT9B adds to the list of genes that have previously been shown to have an association with prostate cancer, including HOXB13, the 8q24 locus, and BRCA2.

The authors noted, “WNT9B shares an unexpected commonality with the previously established prostate cancer risk genes HOXB13 and HNF1B: they are each required for embryonic prostate development.”

Based on this observation, the investigators then evaluated 2 additional genes, KMT2D and DHCR7, both of which have been shown to cause Mendelian genitourinary developmental defects. Upon meta-analysis, both gene mutations showed nominal associations with prostate cancer.

“Risk for prostate cancer due to pathogenic WNT9B mutation is comparable to risk of breast cancer conferred by pathogenic mutations that are routinely tested for breast cancer care,” added Smith, who is an associate professor of medicine in the division of genetic medicine at Vanderbilt University Medical Center in Nashville, Tennessee.² “Knowledge of inherited mutations can guide selection of effective treatments and can carry broader implications for a family.”

The next step in this research, according to the news release, will be to determine if these gene mutations have any impact on clinical outcomes.

References

1. Dupont WD, Jones AL, Smith JR. Coding variants of the genitourinary development gene WNT9B carry high risk for prostate cancer. JCO Precis Oncol. 2025:9:e2400569. doi:10.1200/PO-24-00569

2. Inherited gene elevates prostate cancer risk in affected families. News release. Vanderbilt University Medical Center. January 27, 2025. Accessed January 29, 2025. https://www.newswise.com/articles/inherited-gene-elevates-prostate-cancer-risk-in-affected-families