ZIA BC 010624 (ZIA) | |||
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Title | The Molecular Profile of Prostate Tumors in African-American Men | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Ambs, Stefan | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $244,121 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Interferon (30.0%) |
Prostate (100.0%) | ||
Research Type | |||
Cancer Progression & Metastasis Endogenous Factors in the Origin and Cause of Cancer |
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Abstract | |||
Previously, we generated gene expression profiles of primary prostate tumors resected from African-American and European-American patients. Analyzing the resulting dataset, we identified gene expression differences between African-American and European-American patients that portray the existence of a distinct tumor microenvironment for these two patient groups. Many of the differently expressed genes were immune-regulatory. These observations have been replicated by others. Perhaps most unexpected was the presence of a distinct interferon signature in many of the African-American tumors. As now shown by us, this signature is closely related to an interferon-related DNA damage resistance signature (IRDS) that predicts resistance to chemotherapy and radiation. Interestingly, IRDS has also been linked to the pro-metastatic epithelial to mesenchymal transition of cancer cells. Thus, IRDS may promote the metastatic process in certain circumstances. To further understand the possible origin of the detected immunobiological differences in tumors of African-American and European-American prostate cancer patients, we started with the evaluation of blood-based immune cell and inflammation marker profiles of African-American and European-American prostate cancer patients and age-matched population-based controls with a focus of immune cell subpopulations that have immune-regulatory functions in cancer biology. It was the hypothesis of this project that immune cell subpopulations that have immune-regulatory functions in cancer biology are different in abundance in these two population groups. This study did not find that any of the investigated immune cell subpopulations (myeloid-derived suppressor cells, T- and B-cell-derived suppressor cells, dendritic cell subpopulations and polarized macrophages) were different in abundance comparing the blood samples from African-American and European-American prostate cancer patients. In contrast, we observed that levels of the inflammation marker, c-reactive protein or CRP, were significantly higher in both African-American patients and controls when compared to European-American patients and controls, indicating the presence of a systemic low grade inflammation in African-American cancer patients and also healthy men. Because vitamin D modulates inflammatory and immune responses and its levels are lower in African-American than European-American men, we are currently designing a study that will perform an integrative analysis of inflammatory and immune biomarkers, vitamin D, and ancestry to examine systemic inflammation as a prostate cancer risk factor in 2000-3000 men of African descent. This study is aimed to investigate whether systemic low-grade inflammation is a prostate cancer risk factor in men of African descent and correlates with vitamin D status, West African ancestry, genetic susceptibility, and aggressive disease. In support of this hypothesis, preliminary results from our NCI Maryland prostate cancer study indicate that regular aspirin use significantly decreases disease risk and the diagnosis of advanced stage disease specifically among AA men. In addition, we are examining whether the development of the IRDS signature and systemic inflammation could be functionally linked to a germline variation that frequently occurs in men of African ancestry but is rather uncommon in men of European ancestry and encodes a novel interferon termed interferon lambda 4. The presence of an interferon gene signature in prostate tumors also suggested a possible involvement of either a viral infection in disease pathology or the reactivation of endogenous retroviruses in the tumor microenvironment. This hypothesis was further supported by our finding that the interferon signature in prostate tumors coincides with a gene signature of retroviral activation. Thus, we started a project exploring the presence of viral infections and the reactivation of endogenous retroviruses in tumors from African-American |