MON-328 - Genetically Determined Deficiency of Progesterone and Vitamin D Is A Significant Risk Factor for Early Onset Prostate Cancer.

Introduction. In this study, we aim to demonstrate the significance of a functional deficiency in progesterone and vitamin D, caused by carrying haplotypes associated with low sensitivity of the PGR and VDR receptors and low activity of the CYP27B1 enzyme (synthesis of the active form of vitamin D, calcitriol), as a risk factor for early-onset prostate cancer.

Objective. To investigate the influence of common haplotypes of the PGR (progesterone receptor), VDR (vitamin D receptor), and CYP27B1 (1α-hydroxylase) genes, which are responsible for tissue sensitivity to progesterone and functional vitamin D deficiency, on the risk of developing prostate cancer in patients under 55 years of age.

Patients and Methods. This case-control study included 90 participants: a study group of 45 individuals with newly diagnosed prostate cancer under the age of 55, and a control group of 45 individuals aged 55-70 without a prostate cancer diagnosis at the time of the study. All participants were genotyped for five function-reducing variants: PGR rs1042838, PGR rs608995, VDR rs1544410, VDR rs2228570, CYP27B1 rs4646536. Genotyping was performed by pyrosequencing using test systems manufactured by "Allele" LLC. The association between genetic variants and clinical diagnosis was assessed by calculating odds ratios (OR) using dominant and recessive models.

Results. Function-reducing variants in vitamin D metabolism genes showed an association with a higher risk of prostate cancer: VDR rs1544410 – OR=1.9 (CI 0.8-4.4); VDR rs2228570 – OR=1.2 (CI 0.6-3.0); CYP27B1 rs4646536 – OR=2.3 (CI 0.98-5.6). For these variants, a higher frequency of alternative homozygotes was observed in the study group compared to the control group (17.8%, 22.2%, 48.9% vs. 4.4%, 8.9%, 28.9%, respectively). An association with prostate cancer risk was shown for the PGR rs1042838 variant – OR=1.97 (CI 0.7-5.6). Notably, no patients in the study group had the normal CYP27B1 GG genotype (high 1α-hydroxylase enzyme activity), and the control group lacked homozygotes for both receptor-sensitivity-reducing alleles PGR rs1042838 - AA and PGR rs608995 - AA. The frequency of compound heterozygotes PGR rs1042838 CA/PGR rs608995 CA was higher in the study group (26% vs. 15%, respectively). Calculation of the cumulative risk for the PGR/VDR/CYP27B1 haplotype showed that in the absence of function-reducing variants in these genes, the risk of prostate cancer is 3.37 times lower – OR= 0.28 (CI 0.10-0.80).

Conclusions. The results of this study demonstrated the influence of function-reducing variants in vitamin D metabolism (VDR, CYP27B1) and progesterone receptor (PGR) genes on the risk of developing early-onset prostate cancer. Our research highlights the necessity of a combined analysis of genetic variants within haplotypes for more comprehensive risk prediction and opens prospects for a preventive approach to managing high-risk patients.

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