Abstract
The Institute of Medicine concluded that not all segments of the U.S. population have equally benefited from the advances in our knowledge and treatment of cancer. As one consequence, African American men still have the highest prostate cancer mortality among all U.S. racial and ethnic groups (1). The disparity in prostate survival between African American (AA) and European American (EA) patients was found to persist in randomized clinical trials (2), raising the possibility that intrinsic differences in tumor biology may contribute to the survival disparity between these two patient cohorts. Our group seeks to identify differences in tumor biology that may exist between AA and EA patients, and how these differences may either influence the presentation of the disease (e.g., causing a more aggressive disease among AA patients), or influence the response to therapy (e.g., causing an inferior response among AA patients). We hypothesize that these differences, if they exist, are not likely to be generalizable, meaning that all AA patients are equally different from all EA patients. Rather we believe that certain biologically derived poor outcome factors are more prevalent among AA patients than EA patients, and that future clinical
interventions will have to target these factors across all patient groups. Analyzing prostate tumors, we identified gene expression differences between AA and EA men that portray the existence of a distinct tumor microenvironment in these two patient groups. Many of the genes identified are related to the immune system. Our findings suggest that AA and EA patients might respond differently to cancer therapy. Perhaps most significant is the presence of an interferon signature in many of the AA tumors. This signature is almost identical with a recently discovered interferon-related DNA damage resistance signature (IRDS) and predicts resistance to chemotherapy and radiation (3).
In our study, we examined the tumor biology of prostate cancer comparing AA patients with EA patients using large scale gene expression profiling and found significant differences in gene expression that are consistent with race/ethnic differences in tumor immunobiology (4). Numerous differentially expressed genes clustered in pathways related to immune response, host defense, cytokine signaling and chemotaxis, and inflammation. We did not find that previously identified marker genes for prostate cancer were differently expressed between the two patient groups. This observation suggests that the most common alterations in gene expression that occur in prostate carcinogenesis do not develop differently in AA and EA men. Intriguingly, a prominent interferon gene signature was detected in the AA tumors that may relate to either an unknown etiologic agent in disease pathology (e.g., a viral infection), to tumor-stroma interactions (5), or to specific genomic alterations in the cancer cells. The latter hypothesis is supported by our finding that the interferon signature can persist in cultured primary prostate cancer epithelial cells. Moreover, a recent report showed that DNA copy number alterations in AA tumors may prominently affect genes related to immune response (6).
It is also plausible that some of the detected gene expression differences in our study are partly caused by common genetic variations. There are now several studies that observed differences in gene expression among population groups because of common genetic variations (7-9). Functional genetic variants in key inflammatory and immune-related genes can show large frequency differences between population groups because of their different ancestry (10). We hypothesize that population group-specific functional genetic polymorphisms may commonly be found in genes that regulate the immune system and host defense and developed because of the necessary adaptation of the host to become resistant to infections unique to a given environment. An example is the existence of functionally significant polymorphisms in the NOS2 (NOS2A) and Duffy antigen (DARC) genes that evolved in Africa to resist Malaria infections. Both genes may have key functions in tumor biology. One polymorphism abolishes Duffy antigen expression (11). Interestingly, this antigen also serves as a chemokine receptor and reservoir (e.g., for IL-8 and MCP-1), and specifically targets the tumor suppressor KAI1 (12). Two previous studies investigated gene expression variations between individuals with European ancestry and individuals with African ancestry (Nigeria) using lymphoblastoid cell lines (8, 9). Analogous to our prostate cancer study, the authors assessed the enrichment of biological processes and pathways by genes that are differentially expressed by race/ethnicity. Notably, processes related to antimicrobial humoral response, inflammation mediated by chemokines and cytokines, histamine H1 receptor-mediated signaling pathway, toll-receptor signaling pathway, and the VEGF signaling pathway were identified. The results from the two studies suggest that differences in the genetic background between healthy volunteers of European ancestry and those from Nigeria can cause gene expression differences affecting host immune response, inflammation and chemotaxis, and angiogenesis. These findings are consistent with our study, and while preliminary, raise the possibility that differences in common genetic variations among population groups may lead to group-specific alterations in cancer-related pathways that control host response, inflammation, and tumor angiogenesis.
References
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Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):PL02-02.
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