We previously reported that men with naturally red hair had a significantly lower risk of prostate cancer (HR=0.46, 95% CI 0.24-0.89) compared with the most prevalent hair color, light brown (Br J Cancer 2013;109(3):747-750). The red hair phenotype is encoded by variants in the melanocortin-1-receptor (MC1R) gene that controls expression of the eumelanin and pheomelanin pigments. In order to re-examine this association through the relatively unbiased Mendelian randomization approach, we examined single nucleotide polymorphisms (SNPs) in and near MC1R in relation to prostate cancer risk using data from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. The analysis includes 38,868 men diagnosed with prostate cancer and 25,210 controls from 35 studies participating in PRACTICAL Consortium (Nat Gen 2014;46(10)1103-1109). Logistic regression modeling was used to estimate the odds ratio (OR) and confidence interval (CI) for the per allele prostate risk associations with 148 genotyped SNPs and 164 imputed SNPs. Variants demonstrating nominal significance (alpha-error p<0.05) as well as those reaching a stringent Bonferroni threshold of p<0.0003 adjustment for multiple comparisons were examined. We identified prostate cancer risk associations with 30 genotyped and 36 imputed polymorphisms that were nominally significant, three of which achieved Bonferroni significance and were in a region of 16q24.3 that includes MC1R, GAS8 (growth arrest specific-8, an alleged tumor suppressor that is deleted in some prostate cancers), and transcription factor-25 (TCF25). These were rs4628973 and rs3743824 that were in high LD (r2=0.931; prostate cancer risk associations p=0.00029 and 0.00023, respectively), as well as rs6500461 that was independently associated with risk (r2=0.20 with rs4628973; p=0.00020). This large-scale Mendelian randomization analysis suggests genetic variants near MC1R, which directs melanocyte melanin synthesis, secretion and human pigmentation, may be associated with risk of prostate cancer.

Citation Format: Stephanie J. Weinstein, Tracy M. Layne, Jiaqi Huang, Eric Karlins, Stephen J. Chanock, Demetrius Albanes, the PRACTICAL Consortium. Genetic variants in the 16q24.3 region of melanocortin-1-receptor (MC1R) and prostate cancer risk: A Mendelian randomization analysis of 39,000 cases and 25,000 controls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1271. doi:10.1158/1538-7445.AM2017-1271