Abstract
Abstract Background: MicroRNAs (miRNAs) have recently been identified as promising markers to study for genetic susceptibility to cancer and have potential clinical utility in prostate cancer (PCA) risk assessment. Single nucleotide polymorphisms (SNPs) in genes encoding miRNA target sites for mRNA may interfere with miRNA binding to the mRNA, leading to aberrant mRNA expression and carcinogenesis. Here, we studied SNPs in 4 genes (ALOX15, IL-16, IL-18, and RAF1) with biologic relevance to PCA that encode mRNA with miRNA target sites. We evaluated these SNPs for association to race and time to PCA diagnosis in men at high risk for PCA (men with a family history [FH] of PCA and African American [AA] men) enrolled in a prospective early detection program to determine their future role in personalizing PCA early detection. Methods: The Prostate Cancer Risk Assessment Program (PRAP) is a prospective screening program for high risk men. PRAP has > 800 participants, and 60% are AA. Average follow-up is 4 years. Eligibility for PRAP includes men ages 35-69 years with one first degree relative with PCA, two second degree relatives with PCA on the same side of the family, any AA man regardless of FH of PCA, and men with BRCA1/2 mutations. Criteria for biopsy and biopsy approach have been reported previously. Genotyping methods included either Taqman® SNP Genotyping Assay (Applied Biosystems) or pyrosequencing. Standard sequencing was performed on 2% of the samples to confirm genotype calls. Standard statistical methods were used to determine risk-genotype distributions. Cox models were used for time to PCA diagnosis by risk genotype. Results: SNP genotypes were available for the following: n=749 for ALOX15, n=754 for RAF1, n=753 for IL-16, and n=766 for IL-18. There was a significant difference in distribution of miRNA target SNPs by race in ALOX15 (p<0.0001), RAF1 (p<0.0001), and IL-18 (p<0.0001). Among 278 AA men with > one follow-up visit, the TT genotype at rs1131445 in IL-16 was found to be significantly associated with earlier time to PCA diagnosis vs. the CC/CT genotypes (p=0.013). Hazard ratio after controlling for age and PSA for TT vs. CC/CT among AA men was 2.27 (p=0.0091). In addition, among 283 AA men with > one follow-up visit, the TT genotype at rs360727 in IL-18 was found to predict earlier time to PCA diagnosis vs CC/CT (p=0.017). Hazard ratio for PCA after controlling for age and PSA for TT vs. CC/CT among AA men was 4.44 (p=0.042). No trends in time to PCA diagnosis were seen among Caucasian men in PRAP for any of the miRNA target SNP genotypes. Conclusions: Genetic polymorphisms in miRNA target sites in IL-16 and IL-18 may be informative of time to PCA diagnosis among AA men enrolled in PCA risk assessment and may help to tailor screening and prevention recommendations in the future. Further study among high-risk men is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1820. doi:10.1158/1538-7445.AM2011-1820
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