Epigenetic analysis identifies factors driving racial disparity in prostate cancer

Abstract

Prostate cancer (PCa) is the second most leading cause of death in men worldwide. African American men (AA) represent more aggressive form of PCa as compared to Caucasian (CA) counterparts. Evidence suggests that genetic and other biological factors could account for the observed racial disparity. We analyzed the cancer genome atlas (TCGA) dataset (2015) for existing epigenetic variation in AA and CA prostate cancer patients, and carried out Reduced Representation Bisulphite Sequencing (RRBS) analysis to identify global methylation changes in AA and CA prostate cancer patients. The TCGA dataset analysis revealed that the epigenetic heterogeneity could be categorized into 4 classes, where AA associated primarily to methylation cluster 1 (p value 0.048), and CA associated to methylation cluster 3 (p value 0.000146). We identified enrichment of Wnt signaling genes in both AA and CA, however they were differentially activated in terms of canonical and non-canonical Wnt signaling pathway activation. This was further validated using the GenomeDx expression data. Our RRBS data also suggested distinct methylation patterns in AA compared to CA, and in part validated our TCGA findings. Survival analysis using the RRBS data suggested hypomethylated genes to be significantly associated with recurrence of prostate cancer in CA (p=6.07x10 -6 ) as well as in AA (p=0.0077). Overall, the observed racial disparity in the molecular mechanism involved in the pathogenesis of prostate cancer suggests diverse heterogeneity that potentially could affect survival and should be considered during prognosis and treatment.Prostate cancer (PCa) is one of the most prevalent malignancies affecting men (Fitzmaurice et al., 2013) [1] and the second-most leading cause of cancer-related death for men in the US [2,3].According to Surveillance, Epidemiology, and End Results (SEER) there is a decline in prostate cancer incidence over the past few decades [4]. However, African American men (AA) present early onset of the disease with high-grade tumor, aggressive metastasis potential with increased risk of recurrence, and have worse survival outcomes when compared to their CA counterparts [5][6][7][8]. It is suggested that racial disparity in PCa is influenced by socioeconomic status, diet and lifestyle [9][10][11], but several lines of evidence indicate that biological factors like genetic and epigenetic factors are major contributors to this disparity [8,12]. Such factors include ERG rearrangement, PTEN deletion, SPINK1 overexpression, SPOP mutation and 8q24 SNPs [13,14]. Furthermore, PCa in AA is associated with higher testosterone levels and prominent immune related tumor biology [15][16][17], with tumor microenvironment dynamics associated with more aggressive phenotype in AA when compared to CA [18].Aberrant DNA methylation is an important epigenetic modulation that has been implicated in PCa etiology and disease progression [19]. Methylation changes primarily occur in CpG islands sequestered in the promoter regions [20]. Whole genome methylati...

A biosocial return to race? A cautionary view for the postgenomic era

“…Despite heterogeneities in methodology and geographic focus, all 49 studies mirror the growing perception that epigenetic markers, and particularly DNA methylation (98%; along with one including RNA non‐coding, Li et al, 2020), are a potential basis for explaining ethnic or race‐based differences in health, disease incidence, aging, or reactions to exposures or drugs (Adkins et al, 2011; Barfield et al, 2014; Davis Lynn et al, 2019; Heyn et al, 2013; Li et al, 2020; Needham et al, 2015; Rai et al, 2019; Rawlik et al, 2017; Song et al, 2015). As one study claims, “DNA methylation diversity is a source of variability in human groups at macro and microgeographical scales” (Giuliani et al, 2016; similarly McKennan et al, 2020) and, given that it is considered “highly divergent between populations” (Fraser et al, 2012) can be used to elucidate variation in biological traits or different effects of environmental exposures on racially defined populations: That is, using the terminology of these studies, African American, European, Caucasians (sic), Hispanic, Chinese, or Western (see Table S1, column 3 for complete overview).…”

“…Only three articles (6%) mention or recognize the importance of wider socio‐structural factors as “drivers of racial health differences” (Pepin et al, 2021; see also Lynn et al, 2019, Tsegaselassie et al, 2021). Reversibility is explicitly highlighted by 14 articles (28%) but most discussions of this are brief and often limited to the conclusion, with occasional reference to prospective pharmaceutical or therapeutic interventions (Chan et al, 2017; Demerath et al, 2015; Devaney et al, 2015; Enokida et al, 2005; Lynn et al, 2019; Okosun et al, 2000; Pepin et al, 2021; Pheiffer et al, 2020; Rai et al, 2019; Salihu et al, 2016; Tajuddin et al, 2019; Wang et al, 2016; Wiley et al, 2013; Zhu et al, 2016). v One significant exception is a study by Giuliani et al (2016) that emphasizes reversibility and variability as a theme throughout the article.…”

Exploiting the tumor immune microenvironment and immunometabolism using mitochondria‐targeted drugs: Challenges and opportunities in racial disparity and cancer outcome research

“…84 The importance of epigenetic events in racial disparity is increasingly recognized. [85][86][87][88] One of the primary characteristics of cancer cells is altered metabolism (i.e., the Warburg effect). Inhibitors of glycolytic metabolism in tumors affect epigenetic modifications.…”

MethBank 4.0: an updated database of DNA methylation across a variety of species

“…Taking prostate cancer as an example, there are 59 featured DMGs curated from 5 publications (Figure 3B ) ( 32–36 ). Among them, there are 42 intersections with differential analysis results of project HRA000099 in the Data module of MethBank 4.0, primarily including the key androgen-responsive genes such as EGR1 , AR , KLK3 , and FOLH1 ( 32 , 33 , 36 ) (Figure 3D ). These curated DMGs are enriched in prostate cancer-related pathways including prostate gland development and columnar/cuboidal epithelial cell differentiation (Figure 3E ).…”