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 | $149,910 | Project Dates | null - null |
Fiscal Year | 2018 | 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 possible presence of a systemic low-grade inflammation in African-American cancer patients, and also healthy men. We recently observed that aspirin use significantly reduces the risk of aggressive prostate cancer in African-American men. Because of this observation, we will test if the tumor biology of prostate cancer patients who are regular aspirin users is different from patients who do not take aspirin. 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 (IFNL4 rs368234815-dG). Preliminary data show that patients with the dG allele, which is significantly more common in African than European populations, have an increased occurrence of IRDS. 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. Currently, there is no evidence that a viral infection is a cause of prostate cancer, although a meta-analysis of 26 tissue-based case-control studies reported an association between human papillomavirus positivity and the disease. Additionally, RNASEL, a gene that protects against viral pathogens, may have an important tumor suppressor function in prostate cancer. Because of our observation that viral infection-related host factors are associated with prostate cancer in African-American men, we begun to |