Associations between RNA splicing regulatory variants of stemness-related genes and racial disparities in susceptibility to prostate cancer.

ABSTRACT

Evidence suggests that cells with a stemness phenotype play a pivotal role in oncogenesis, and prostate cells exhibiting this phenotype have been identified. We used two genome-wide association study (GWAS) datasets of African descendants, from the Multiethnic/Minority Cohort Study of Diet and Cancer (MEC) and the Ghana Prostate Study, and two GWAS datasets of non-Hispanic whites, from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the Breast and Prostate Cancer Cohort Consortium (BPC3), to analyze the associations between genetic variants of stemness-related genes and racial disparities in susceptibility to prostate cancer. We evaluated associations of single-nucleotide polymorphisms (SNPs) in 25 stemness-related genes with prostate cancer risk in 1,609 cases and 2,550 controls of non-Hispanic whites (4,934 SNPs) and 1,144 cases and 1,116 controls of African descendants (5,448 SNPs) with correction by false discovery rate ≤0.2. We identified 32 SNPs in five genes (TP63, ALDH1A1, WNT1, MET and EGFR) that were significantly associated with prostate cancer risk, of which six SNPs in three genes (TP63, ALDH1A1 and WNT1) and eight EGFR SNPs showed heterogeneity in susceptibility between these two racial groups. In addition, 13 SNPs in MET and one in ALDH1A1 were found only in African descendants. The in silico bioinformatics analyses revealed that EGFR rs2072454 and SNPs in linkage with the identified SNPs in MET and ALDH1A1 (r2 > 0.6) were predicted to regulate RNA splicing. These variants may serve as novel biomarkers for racial disparities in prostate cancer risk.