Associations of genetic polymorphisms in SLCO transporters with clinical aggressiveness of prostate cancer in the North Carolina-Louisiana Prostate Cancer Project
African-American men (AAs), compared to European-American men (EAs), are more likely to present with more aggressive phenotypes of prostate cancer (PC), characterized by earlier onset and higher rates of progression. Androgen-stimulated androgen receptor signaling is crucial to proliferation and survival of PC cells. It is hypothesized that genetic variations in potential androgen transporters, the solute carrier family of the organic anion transporting peptides (SLCO), may change availability of androgen to PC cells, and contribute to racial differences in PC aggressiveness.
Blood DNA samples and clinical and epidemiological data were requested from the North Carolina-Louisiana Prostate Cancer Project (PCaP), a multidisciplinary population-based, case-only study of racial/ethnic differences in PC aggressiveness. Selection of tag single nucleotide polymorphisms (SNPs) for all 11 members of SLCO family was based on HapMap data for AAs and EAs, requiring r2≥0.8 with minor allele frequency ≥ 5%. The panel of SNPs also included potential functional SNPs selected from the literature and 128 ancestry informative markers for population structure analysis. Genotyping was performed using Illumina GoldenGate. A total of 2050 research subjects (993 AAs and 1057 EAs) were studied. Logistic regression was conducted in AAs and EAs separately, adjusting for age, study site, family history of PC and African ancestry proportion. In addition, 50 pairs of PC and adjacent benign tissues were requested from Roswell Park Cancer Institute and expression of SLCO transporters was determined using qRT-PCR.
Significant SNPs after False Discovery Rate correction for multiple comparisons were found in SLCO2A1 and 5A1. Three SNPs in 2A1 were associated with reduced tumor aggressiveness and/or low Gleason score; the associations were primarily observed in AAs. In contrast, four SNPs in 5A1 were associated with high clinical stage; and the associations were primarily found in EAs. The associations with rs9917636 and rs3811662 in 2A1 and rs16919172 in 5A1 significantly differed by race (P for interaction <0.05). In human prostate benign and cancer tissues, 2A1 and 5A1 were the most expressed SLCO transporters at the mRNA levels. </p>
Among 11 SLCO family members, 2A1 and 5A1 may play an important role in prostate cancer. Genetic variations in SLCO2A1 and 5A1 may contribute differently to prostate cancer aggressiveness in AAs and EAs.
Funding: Supported by DOD Healthy disparity award W81XWH-14-1-0453 and RPCI Alliance Foundation. The study used shared resources supported by RPCI's Cancer Center Support Grant from the NCI P30CA016056.