The existence of racial disparities in prostate cancer is generally acknowledged, but the predominant factor influencing these disparities remains contested. Some believe that socioeconomic variables are primarily responsible for the worse outcome in AA PCa patients[24
], while others recognize the possibility of biologic heterogeneity in AA versus CA tumorigenesis [8
]. In the current study, we utilized an integrated genome wide approach to demonstrate that AA and CA prostate tumors exhibit molecular differences with regard to DNA copy number and gene expression. Thus, it is possible that AA and CA tumors harbor distinct areas of genomic instability or sensitivity to selective pressures that results in characteristic DNA copy number alterations. This instability may represent an inherited source of differential risk or a differential response to environmental factors between the two groups that might influence the outcome of disease.
The results of our integrated genomic analyses are consistent with those from two previous studies that identified molecular differences between AA and CA prostate tumors using gene expression profiling[25
]. Our study makes the additional finding that DNA copy number alterations are a likely mechanism for these observed differences in gene expression. The gene expression study by Wallace and colleagues of 69 tumors from AA and CA patients revealed a relatively short list of 162 transcripts differentially expressed between the two cohorts[26
]. Further analysis resulted in the creation a two-gene classifier (CRYBB2
) that was able to accurately separate AA from CA, although the role of these two genes as drivers of tumorigenesis in AA or CA is unclear at the present time. Another study of gene expression differences between AA and CA tumors identified cell death regulatory protein TCEAL 7
as differentially overexpressed in CA versus AA tumors[25
]. This finding led authors to speculate that TCEAL 7
may play an oncosuppressive role that contributes to the relatively aggressive nature of PCa in AA.
Functional annotation and pathway analysis of genes mapping to the 4 genomic regions of overlap in our two independent cohorts revealed significant enrichment for ontologic annotations related to immune function. Included among the genes annotated as Immune System Processes
, and AKT-1
. It is notable that two other published, independent gene expression profiling studies also noted enrichment of immune-related genes in their comparison of AA and CA tumors [25
]. Specifically, immunoglobulin heavy constant mu (IGHM
), which maps to 14q32.33, was one of the top 20 genes with higher expression in AA compared to CA tumors in the study by Wallace[26
]. The list of differentially expressed genes reported in the Reams study showed significant enrichment of pathways related to interleukins[25
]. Taken together, data suggest that differences in host immunity may influence the natural history of PCa in AA and CA patients, and our results show that these differences are likely present in the cancer genome.
These findings are particularly relevant in light of the recent emergence of immunotherapy as a potential treatment for PCa. A dendritic cell vaccine has gained approval by the Food and Drug Administration (FDA) for use in hormone refractory metastatic prostate cancer patients, and the first phase I trial of a hybrid peptide vaccine as adjuvant therapy for metastatic and non metastatic patients with was recently completed[27
]. Based on our genomic analysis of AA and CA tumors, it is possible that AA and CA patients might respond differently to immuno-based therapies. As the use of immunotherapy expands to include a larger population of both primary and metastatic PCa patients, it will be important to consider how differences in host immunity might influence the response to therapy or the molecular readouts of treatment activity such as T cell proliferation.
The large range of chromosomal alterations observed in solid tumors have in the past made it difficult to identify a signature of alterations that are common in prostate cancer in the way that characteristic changes have been identified in lymphoid malignancies. Without such a signature, there is no basis for devising molecular targets for treatment, diagnosis, or prognostication that can be consistently used for specific groups of patients. It is noteworthy that in our study, 4 genomic regions were reproduced in an independent group of tumors using a different platform. Two of these regions (5p15.33 and 16p11.2) have been previously reported as common areas of genomic gain in prostate cancer. In one series of 18 prostate cancer cell lines and xenografts, 39% of samples had copy number gain at 5p15.33 and 39% had gains at 16p12.2-p11.2[29
]. As in our study, the authors were able to demonstrate concordance between copy number gain and gene overexpression, most notably in genes mapping 16p12.2-p11.2 (RBBP6, RGS11, and RABEP2). RABEP2
maps to 16p11.2 and is a GTPase binding effector protein that has not been previously associated with PCa. The finding of copy number gains at 16p11.2 and overexpression of RABEP2
in this previous study of PCa cell lines and in our current study of human PCa tissues is reassuring of the validity of the data.
Both array CGH and gene expression arrays are methodologies with relatively high false positive rates. Correlation of DNA copy number and gene expression data enables one to filter out many false positive results and provides a basis for correlating gene expression changes with a specific altered genomic mechanism. In this regard, we report a high concordance between DNA copy number and gene expression in all of the 27 most significantly altered genomic regions between AA and CA prostate tumors. Lower concordance rates observed in other studies[30
] may reflect differences in the regulation of expression of the genes observed in those studies or may be reflective of the greater difficulty inherent in working with RNA leading to artifacts. In our study, we prioritized sets of genes for pathway analysis based on the chromosomal regions that differentially affected AA and CA tumors in two independent patient cohorts. Of note, 14q32 was gained in CA patients in the initial cohort but gained in AA patients in the validation cohort. This discrepancy might be due to differences in the resolution and genomic region coverage of the BAC-based and oligo-based array platforms. It is possible that the BAC array missed the more focal copy number gain detected in the AA tumors by oligo-array. The published data showing that IGHM
, which maps to 14q32.33, is significantly overexpressed in AA tumors[26
] lend support to our oligo-based array finding that 14q32.33 shows significant copy number gains in AA tumors.
In conclusion, our study reveals molecular differences that characterize AA and CA PCa tumorigenesis. Pathway analysis revealed significant over-representation of inflammation and immunobiology-related genes. Further studies are warranted to adequately assess the clinical implications of these observed differences.
The authors confirm that there are no conflicts of interest.