A clinical challenge in prostate cancer (PCa) is identifying the characteristics of primary lesions that give rise to metastatic disease so that patients receive immediate treatment. Genetic variation in microRNA (miRNA) genes can affect mature miRNA biogenesis and/or mRNA targeting, which can consequently influence cancer susceptibility and progression. We identified an under-studied genetic variant (rs13136737, G/T) that is near the 3’ end of the polycistronic primary miRNA, hsa-miR-302/367, which we show to be biofunctional. In this study we investigated the biological effects and clinical consequences of this sequence variant in PCa. We found that production of mature miRNAs from the hsa-miR-302/367 cluster is dependent on rs13136737 genotype, and that the T-allele primary transcript is inefficiently processed with respect to production of mature miR-302d and miR-367. To evaluate the consequences of rs13136737 germ line variation we genotyped the locus in a mixed-race cohort of prostate cancer patients and tested for an association with cancer stage at diagnosis as an indicator of aggressiveness. We observed an age-dependent association between rs13136737 genotype and increased risk of advanced stage PCa which was present only in younger men [<65 years, OR = 3.13, 95% confidence interval 1.46 – 7.52; p=0.003] and replicated this association in an independent data set of African-American men [OR: 1.58; 95% confidence interval 1.10 – 2.26; p=0.013]. When the cancer risk of the polymorphism was stratified with age in an African American population, the 45-54 years of age group shows significance (p=0.0374) whereas there was no significant association in older men. This suggests SNP rs13136737 T allele is associated with risk in early-onset PCa patients. The consistency of this result in discovery and validation datasets, which varied substantially in their racial composition, suggests that rs13136737 genotype may be a robust biomarker for risk of advanced stage PCa among younger men. The rs13136737 risk allele (T) occurs at high frequencies in European, South Asian, Hispanic, and Native American populations (0.51, 0.52, 0.57, and 0.71, respectively) and at relatively low frequency in African/African-American populations (0.12). This indicates that the clinical utility of rs13136737 will be sensitive to patient ancestry due to variation in the frequency of the risk allele.
Citation Format: Ronald L Heimark, Kelsey Guest, Virginia Ware, Kari Hernandez, Brenna Rheinheimer, Jessica M Patnode, Raquel Dias, Mitchell Sokoloff, Jason A Wilder. A common microRNA-flanking variant (rs13136737) in hsa-miR-302/367 affects risk of prostate cancer progression in young men [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C049.