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

作者：Wang Yanru; Freedman Jennifer A; Liu Hongliang; Moorman Patricia G; Hyslop Terry; George Daniel J; Lee Norman H; Patierno Steven R; Wei Qingyi^*

来源：International Journal of Cancer, 2017, 141(4): 731-743.

DOI：10.1002/ijc.30787

• cancer disparities among racial groups
• single-nucleotide polymorphism
• stemness
• prostate cancer susceptibility
• RNA splicing

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 (r(2)>0.6) were predicted to regulate RNA splicing. These variants may serve as novel biomarkers for racial disparities in prostate cancer risk.
What's new? The mechanisms underlying prostate cancer disparities among racial groups remain largely unknown. Here, the authors assessed the role of stemness-related genetic variants in racial differences in prostate cancer risk by re-analyzing published datasets from four genome-wide association studies of African descendants and non-Hispanic whites. They found that SNPs in TP63, ALDH1A1, WNT1, MET and EGFR were significantly associated with prostate cancer risk and showed differences between the racial groups. Bioinformatics analyses revealed RNA splicing-regulatory SNPs in EGFR, MET and ALDH1A1 as possible novel biomarkers that may provide new insights into the molecular mechanisms underlying racial disparities in prostate cancer risk.

• 出版日期2017-8-15