Photo Credit: Dr. Microbe

The following is a summary of “Metastatic prostate cancer is associated with distinct higher frequency of genetic mutations at diagnosis,” published in the November 2023 issue of Urology by Al-Toubat, et al.

For a study, researchers looked into DNA changes that are linked to metastatic prostate cancer (PCa) by comparing data from next-generation sequencing (NGS) between men who had or did not have metastatic disease at the time of diagnosis. They looked through the GENIE list for men identified with PCa from the American Association for Cancer Research Project. Patients were put into two groups: those with invasive disease (M1) and those without it (M0). They used SPSS V28 to examine the difference in the number of genetic changes between the two groups and what those mutations mean for the future. They used a frequency rate of more than 5%, and P values less than 0.05 were considered statistically significant to keep the over 95% true positive detection rate. 

Out of the 10,580 patients diagnosed with PCa in the sample, they chose 1,268 patients whose data was complete. Of these, 700 (55.2%) had nonmetastatic PCa, 421 (33.2%) had metastatic castration-sensitive PCa, and 147 (11.6%) had metastatic castration-resistant PCa. The average age at diagnosis was 62.8 years (IQR 56.3–68.4), and the average PSA level in the blood was 8.0 ng/ml (IQR 4.9–20.9) for the whole group. Almost everyone in the group was Caucasian (89.1%). Out of the 561 genes analyzed, 79 (14.1%) had changed. With 35.7% vs. 23.3%, the mutation rate was significantly higher in M1PCa compared to M0PCa (P = 0.001). There were also significantly more mutations in the M1PCa samples (2.59 mut/MB) than in the M0PCa samples (1.96 mut/MB) (P < 0.001). M1PCa patients had a much higher rate of genetic mutations than M0PCa patients. These mutations were found in TP53 (38.73% vs. 17.71% P < 0.001), PTEN (25.70% vs. 11.71% P < 0.001), AR (17.25% vs. 1.43% P < 0.001), APC (11.8% vs. 4.43% P < 0.001), TMPRSS2 (31.5% vs. 11.14% P < 0.001), ERG (23.59% vs. 13.13% P < 0.001), FOXA1 (17.43% vs. 6.33% P < 0.001), MYC (8.45% vs. 2.29% P < 0.001), RB1 (10.39% vs. 2.31% P < 0.001), and CDK12 (8.45% vs. 1.31% P < 0.001). 

The androgen receptor signaling pathway was most often affected out of all the cellular signaling pathways. It was found that men with genetic mutations had a lower chance of life in the group with M1 disease than men without (P = 0.001, log-rank test). Castration-sensitive M1 patients had fewer mutations in AR (57% vs. 4% P < 0.001), TP53 (50.7% vs. 34% P < 0.001), PTEN (35.2% vs. 22.1% P < 0.001), and RB1 (23.9% vs. 4.75% P < 0.001). Castration-resistant M1 patients had a lot more mutations in these genes. On the other hand, changes in SPOP (13.3%), FOXA1 (17.6%), and CDK12 (12% vs. 6.45% P < 0.001) were much more common in M1 patients who were sensitive to castration than in M1 patients who were not sensitive to castration. Patients with M1PCa had different DNA changes compared to those with M0PCa. The changes usually affected androgen receptor signaling and were linked to a shorter life rate. They also found different DNA changes in M1PCa that make it sensitive to castration and immune to it. The results could help them learn more about guys with PCa and improve how they are treated.

Source: sciencedirect.com/science/article/abs/pii/S1078143923003289