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, as well as 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.

Hepatocyte gene expression and DNA methylation as ancestry-dependent mechanisms in African Americans

“…In particular, APOL1 , PTGIS , and PLAT expression levels, which we show to be associated with WAA, have been shown to increase CVD risk and renal disease in AAs. 13,34,35 Other genes associated with WAA include ALDH1A1 , which is involved in alcohol and aldehyde metabolism disorders and cancer risk 11,36,37 ; IL-33 , which is involved in beneficial immune response, 38–40 and VEGFA , which has been linked to renal disease and microvascular complications of diabetes. 7,14,41,42 These findings will require further validation to better elucidate the extent to which the identified pathways affect diseases in AAs.…”

Race as a Contributor to Stromal Modulation of Tumor Progression

“…It is undeniable that many of the exogenous factors could induce somatic, genetic, as well as epigenetic changes occurring within and around cancer cells to alter the biology of tumors and affect racial disparities in incidence and progression. The scientific literature is filled with genetic studies looking at the mutational burden of tumors or genome-wide association studies (GWAS) to explain racial disparities in cancer [ 15 , 16 , 17 ]. There is increasing evidence supporting the notion that the TME may contribute to racial disparities observed in the incidence and outcomes of different types of cancer reported in the AA compared to the EA population [ 18 , 19 , 20 , 21 , 22 ].…”

Genetic variants in SLC22A3 contribute to the susceptibility to colorectal cancer

“…Recently, multiple genome‐wide association studies (GWASs) have reported several genes or loci associated with colorectal cancer susceptibility . For the Asian population, SNP rs7758229 located in the chromosome 6q26‐q27 region was the first discovered to be associated with the risk of distant colorectal cancer in the Japanese population .…”

“…8,9 Recently, multiple genome-wide association studies (GWASs) have reported several genes or loci associated with colorectal cancer susceptibility. [10][11][12][13][14] For the Asian population, SNP rs7758229 located in the chromosome 6q26-q27 region was the first discovered to be associated with the risk of distant colorectal cancer in the Japanese population. 15 However, in our previous validation study within the Chinese population, we found that rs7758229 showed no relationship with colorectal cancer risk.…”