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.

Trial registration: ClinicalTrials.gov NCT02609269.

Conflict of interest statement

The authors declare the following competing interests: Y.L. and E.D. are employees of Decipher Biosciences. R.B.D. has received research funding and has served as a consultant for Decipher Biosciences. P.L.N. has served as a consultant for Decipher Biosciences, Ferring, Bayer, Astellas Medivation, Dendreon, Blue Earth, Nanobiotix, Augmenix, and Infinity Pharmaceuticals. F.F.Y.F. is an employee of PFS genomics and has served as a consultant for Medivation/Astellas, Decipher, Celgene, Dendreon, EMD Serono, Janssen Oncology, Ferring, and Bayer. D.E.S. has served as a consultant for Dendreon. E.M.S. has served as a consultant for Decipher, OPKO Health, Abbvie. K.K.Y. is an employee of Sema4, a Mount Sinai venture company, and has received royalties from Inthera Bioscience. A.K.T. has served as a site-PI on pharma/industry-sponsored clinical trials from Kite Pharma, Lumicell Inc, Dendreon, and Oncovir Inc. He has received research funding (grants) to his institution from DOD, NIH, Axogen, Intuitive surgical, AMBFF, and other philanthropy. A.K.T. has served as an unpaid consultant to Roivant Biosciences and advisor to Promaxo. He owns equity in Promaxo.

Figures

Fig. 1. Comparison of genomic-risk signatures and their grade group associations in AAM and EAM.

a Prognostic differences in AAM vs. EAM. 20 prognostic signatures show similar trends in both groups. Overall, both Decipher (b) and average genomic-risk scores (c) positively correlate with grade groups in both races. b Decipher is higher in AAM with low grades but not different in high-grade tumors. c In contrast, average genomic risk is lower in the AAM with high-grade tumors. AAM African-American men, EAM European-American men. Error bars represent the 95% confidence interval.

Fig. 2. Genome-wide differential expression in AAM and EAM.

a Top 22 genes differentially expressed between the two groups in our cohort with multivariate analysis logistic regression P value <1e−10. Mean difference in TCGA prostate was also shown for these genes to show that these genes show the same directionality. Genes were sorted based on the mean difference between AAM and EAM. b Boxplot of genes differentially expressed in TCGA prostate cohort. Abbreviations as in Fig. 1. Error bars represent the 95% confidence interval.

Fig. 3. Activation of different signaling pathways drives prostate cancer in AAM and EAM.

a The bar plot depicts the log odds of pathways that have a significant association with AAM and EAM after adjusting for clinical variables and false discovery. Many of the pathways more active in the AAM are related to the immune response. Pathways more active in the EAM include those related to DNA repair, glycolytic metabolism, and the cell cycle. b African Americans showed higher inflammation activity and higher expression of CD3, IFNG, IL33, and immune checkpoint inhibitors (PDL2, ICOSLG). Abbreviations as in Fig. 1. Error bars represent the 95% confidence interval.

Fig. 4. Differential expression of DNA repair pathways and genes.

a DNA repair activity and mismatch repair were calculated as mean of genes sets. Both showed lower activity in African Americans. b Key DNA repair genes (MSH2, RAD52, and PRKCD) were the most upregulated in patients. Error bars represent the 95% confidence interval.

Fig. 5. Tumor inflammation heterogeneity in AAM.

Using a set of 124 inflammation and immune-response genes in AAM, consensus clustering revealed a cluster of patients with high expression of immune genes (CD3, CD45, GZMA, B2M, STAT1), nominating this cluster for immunotherapy treatment intervention. AAM African-American men, APF adverse pathology feature.