Comparative analysis of 1152 African-American and European-American men with prostate cancer identifies distinct genomic and immunological differences

Abstract

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.

Why do African–American men face higher risks for lethal prostate cancer?

“…There is a breadth of literature investigating the genomics and molecular biology of PCa in African–American men, but despite this, an accurate understanding of how our knowledge of PCa molecular biology influences clinical outcomes remains elusive. This may, in part, result from the underrepresentation of African–American men in studies focused on genomic profiling, reflected in, for example, a relative paucity of African–American men overall in the PCa Genome Atlas Program (TCGA) [ 5 ▪▪ ]. However, several recent studies have examined the genomic and transcriptome profile of PCa patients allowing a more direct comparison of the racial differences in the molecular pathways underlying PCa oncogenesis and progression and potentially shedding light on future opportunities for screening and therapeutic intervention.…”

“…Rayford et al [ 5 ▪▪ ] performed a comparative analysis of 596 African–American men vs. 556 NHW men with localized PCa undergoing radical prostatectomy, examining their surgical specimens for many parameters related to tumour biology. They also found genomic differences in African–American men vs. NHW men with higher SPINK1 expression (22 vs. 10%), lower ERG expression (23 vs. 41%), significant upregulation of the genes CRYBB2, GSTM3, and those related to inflammatory pathways (e.g.…”

“…Increased SPINK1 but reduced ERG expression has been found in prior recent studies [ 12 ▪▪ , 13 ], but its clinical and prognostic significance is not clear. Interestingly, Rayford et al [ 5 ▪▪ ] also specifically studied expression within fundamental signalling pathways. African–American men had upregulation of gene groups providing functional elements in hypoxic conditions, reactive oxidation, and immune and apoptotic pathways (e.g.…”

“…There is a longstanding debate regarding the cause for these differences, ranging from healthcare access problems, socioeconomic differences resulting in comorbidities that may affect the tumour microenvironment, as well as fundamental differences in tumour biology [ 2 ▪▪ ]. The debate continues with recent evidence supporting the contributions of both socioeconomic issues and tumour biology [ 3 ▪▪ – 5 ▪▪ ]. Two recent epidemiological studies demonstrated that once equal healthcare access was provided to African–American populations, PCa outcomes were the same for African–American and NHW men.…”

“…By contrast, a recent multiinstitutional comparative study analysed 1152 patients (556 NHW men and 596 African–American men) with localized PCa who underwent surgical treatment. They found African–American men had more advanced disease at clinical presentation, with low and favourable intermediate-risk groups having higher risk genomic scores on examination of the surgical disease, as well as significant differences in tumour biology related to inflammatory and metabolic pathways [ 5 ▪▪ ]. The finding of differential expression in immune-related gene pathways has been supported by several recent similar studies assessing comparative genomics and transcriptome profiles in postsurgical tissues from cohorts of African–American and NHW men with localized PCa [ 6 ▪▪ , 7 ▪▪ ].…”