Common genetic variation of the calcium sensing receptor and lethal prostate cancer risk
Menée sur 1 193 patients atteints d'un cancer de la prostate et sur 1 244 témoins, cette étude évalue l'association entre des variants génétiques communs du gène codant pour le récepteur sensible au calcium et le risque de cancer fatal de la prostate en fonction de la consommation de calcium et de la concentration plasmatique de 25-hydroxy-vitamine D
Background: Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether 1) common genetic variation in CaSR was associated with PCa risk and 2) these associations varied by calcium intake or plasma 25-hydroxyvitamin D (25(OH)D) levels. Methods: We included 1193 PCa cases and 1244 controls nested in the prospective Health Professionals Follow-up Study (1993-2004). We genotyped 18 CaSR SNPs to capture common variation. The main outcome was risk of lethal PCa (n=113); secondary outcomes were overall (n=1193) and high-grade PCa (n=225). We used the kernel machine approach to conduct a gene-level multi-marker analysis and unconditional logistic regression to compute per-allele odds ratios (OR) and 95% confidence intervals (CI) for individual SNPs. Results:The joint association of SNPs in CaSR was significant for lethal PCa (p=0.04); this association was stronger in those with low 25(OH)D (p=0.009). No individual SNPs were associated after considering multiple testing; 3 SNPs were nominally associated (p<0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42-0.99): rs6438705; 0.65(0.47-0.89)): rs13083990; and 1.55(1.09-2.20): rs2270916. The 3 non-synonymous SNPs (rs1801725, rs1042636, rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D (OR(95%CI): 0.54(0.31-0.95)). There were no significant associations with overall or high-grade PCa. Conclusions: Our findings indicate that CaSR may be involved in PCa progression. Impact: Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted.