Gene Variant Magnifies Risk of Treatment-Resistant Prostate Cancer


Gene expression may lead to castration-resistant prostate cancer.

New research has verified a link between the HSD17B4 gene and fatal, treatment-resistant prostate cancer. The results of a study published by Cell Reports suggest that men without a subtype of the gene may be more likely to progress to aggressive prostate cancer.

Previously, the team found that mutated HSD3B1 helps prostate cancer bypass treatment and proliferate. They also discovered that this variant can have a significant impact on patient outcomes and overall survival.

Prior studies indicated that the HSD17B4 gene encodes enzymes that inactivate androgens, which should, in theory, prevent prostate cancer; however, the researchers noted that the enzymes are prevalent in advanced prostate cancer, making their overall effect unclear.

Androgen deprivation therapy (ADT) works by blocking the supply of androgens to cells to prevent prostate cancer growth and metastasis. Although ADT is beneficial in early-stage disease, it eventually fails and leads to castration-resistant prostate cancer (CRPC), according to the authors.

Patients with CRPC may continue to receive additional treatments—including corticosteroids, chemotherapy, and immunotherapy—despite the lack of evidence of survival benefit. However, more effective treatment options are needed to prevent unnecessary costs and side effects that come with ineffective treatments.

In the current study, the researchers analyzed HSD17B4 expression in tissue from patients with healthy prostates, localized prostate cancer, and CRPC to determine the gene’s effect in the progression to CRPC.

The authors found that HSD17B4 levels were similar in benign and localized prostate cancer tissue; however, HSD17B4 expression plummeted in CRPC tissue, suggesting that the gene may lower the risk of progression to CRPC, according to the study.

Through further analyses, the researchers discovered that HSD17B4 isoform 2 inactivates androgens and inhibits tumor growth. This isoform was expressed during early stage disease but is suppressed during advanced disease. The authors noted that isoforms have the same DNA but a varied amino acid sequence.

Findings from preclinical models suggest that a lack of isoform 2 can result in advanced CRPC.

If these results translate to humans, patients with prostate cancer may be able to better evaluate their risk of developing aggressive disease.

The authors concluded that additional studies should focus on how HSD17B4 expression is dampened in CRPC and whether it could be used as a biomarker to determine the risk of prostate cancer mortality.

“We are hopeful that these findings will lead to more precise and effective treatments for prostate cancer,” said lead researcher Nima Sharifi, MD. “If men lack a specific isoform of this gene, we may be able to personalize their therapy.”

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