Rare gene mutations predict prostate cancer relapse

Rare and deleterious germline mutations affecting inflammatory response and cellular signaling pathways associate strongly with the time to biochemical recurrence (BCR) after radical treatment in patients with prostate cancer (PrCa), according to a recent study.

“Germline DNA can be sequenced at an early stage of disease or even for healthy individuals, which could enable the prediction of PrCa progression close to, or even in advance of, the point of diagnosis. This would allow clinicians to stratify and differentiate patients who are more likely to relapse, putting them on a different clinical treatment pathway comprising more radical intervention or more frequent follow-up,” the researchers said.

Blood samples were collected from 850 PrCa patients who had undergone radical treatment, and then subjected to whole-genome sequencing. This analysis revealed a total of 15,822 rare variants that were identified as either deleterious or likely deleterious, though no individual mutation was significantly correlated with BCR. All patients in this discovery cohort were enrolled from the Pan Prostate Cancer Group consortium. [Eur Urol 2022;doi:10.1016/j.eururo.2022.05.007]

However, the present sample size of 850 patients was underpowered to detect individual correlations. The researchers looked at gene sets and pathway and found three sets of genes that were significantly associated with BCR, as assessed by Cox proportional hazards models (p<0.05 for all).

The following gene sets were significantly associated with shorter BCR: the PI3K/AKT/mTOR signaling pathway (hazard ratio [HR], 1.55, 95 percent confidence interval [CI], 1.06–2.25; p=0.032), KRAS signaling pathway (HR, 1.35, 95 percent CI, 1.01–1.79; p=0.041), and inflammatory response (HR, 1.35, 95 percent CI, 1.00–1.82; p=0.048).

In contrast, ultraviolet response (HR, 0.71, 95 percent CI, 0.51–0.99; p=0.042) and cholesterol homeostasis (HR, 0.58, 95 percent CI, 0.34–1.00; p=0.048) exerted significantly protective effects against disease relapse. Multiple bootstrap resamplings found these associations to be robust, with all risk-aggravating gene sets retaining an HR >1 in >97 percent of cases.

“To our knowledge, this study is the first to evaluate the association of rare germline mutations across the full exome as opposed to specific plausible candidate genes and provides evidence that germline mutation status is predictive for BCR after radical treatment for PrCa,” the researchers said.

“Importantly, we also show that these gene sets remained independent predictive biomarkers of time to BCR, over and above the inclusion of clinical variables,” they added.

“With additional confirmation and refinement, these signatures could inform prognosis and clinical decision-making,” according to the researchers.

Important study limitations included the small and European-only sample, which curtailed its ability to detect individual gene associations with BCR. In addition, BCR itself was not the strongest surrogate for clinical recurrence and disease progression. Variants of significance were also excluded from the analysis, which instead focused only on mutations with strong evidence for deleterious effect.