Epigenetic analysis identifies factors driving racial disparity in prostate cancer

Abstract

Background Prostate cancer (PCa) is the second most leading cause of death in men worldwide. African‐American men (AA) represent more aggressive form of the disease compared to Caucasian (CA) counterparts. Several lines of evidences suggest that biological factors are responsible for the observed racial disparity. Aim This study was aimed at identifying the epigenetic variation among AA and CA PCa patients and whether DNA methylation differences have an association with clinical outcomes in the two races. Methods and results The cancer genome atlas (TCGA) dataset (2015) was used to identify existing epigenetic variation in AA and CA PCa patients. Reduced Representation Bisulfite Sequencing (RRBS) was performed to identify global DNA methylation changes in a small cohort of AA and CA PCa patients. The RRBS data were then used to identify survival and recurrence outcomes in AA and CA PCa patients using publicly available datasets. The TCGA data analysis revealed epigenetic heterogeneity, which could be categorized into four classes. AA associated primarily to methylation cluster 1 (p = 0.048), and CA associated to methylation cluster 3 (p = 0.000146). Enrichment of the Wnt signaling pathway was identified in both the races; however, they were differentially activated in terms of canonical and non‐canonical Wnt signaling. This was further validated using the Decipher Genomics Resource Information Database (GRID). The RRBS data also identified discrete methylation patterns in AA compared with CA and, in part, validated our TCGA findings. Survival analysis using the RRBS data suggested hypomethylated genes to be significantly associated with recurrence of PCa in CA (p = 6.07 × 10−6) as well as in AA (p = 0.0077). Conclusion Overall, we observed epigenetic‐based racial disparity in PCa which could affect survival and should be considered during prognosis and treatment.

Comparing Urinary Glycoproteins among Three Urogenital Cancers and Identifying Prostate Cancer-Specific Glycoproteins

“… 23 , 24 LRP10 gene has also been reported to be hypermethylated in prostate cancer. 25 MGAM is a maltase-glucoamylase, which is an enzyme that plays a role in the digestion of starch. It is reported to have lower mRNA expression in prostate cancer tissues compared to non-tumorous prostate tissues.…”

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.…”

Racial disparity in prostate cancer in the African American population with actionable ideas and novel immunotherapies

“… 8 , 166 Another interesting study looking at epigenetic differences between AA and CA men found tumors from AA men had hypermethylated loci at MC1, whereas CA men had hypomethylated loci at the MC3 cluster. 167 The result of these epigenetic changes was reduced noncanonical Wnt signaling (Wnt/Ca+2 signaling) in AA men, and activation via the MC3 cluster for CA men. Furthermore, PI3K signaling and inflammatory pathways cause increased expression of MC1 genes.…”

“…Furthermore, PI3K signaling and inflammatory pathways cause increased expression of MC1 genes. 167 Looking at whole blood DNA from AA men, Moses‐Fynn et al 168 assessed DNA methylation status in the genes RARβ2, TIMP3, SPARC, CDH13, HIN1, LINE1, CYB5R2, and DRD2. Overall, they found DNA promoter methylation was more common in AA men, and was linked to a number of clinical and pathological prognostic parameters including Gleason score.…”