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 | $241,801 | Project Dates | 01/01/2003 - 00/00/0000 |
Fiscal Year | 2015 | 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 obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. Analyzing the resulting datasets, 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. Perhaps most unexpected was the presence of a distinct interferon signature in many of the African-American tumors. As now discovered by us, this signature is closely related to an interferon-related DNA damage resistance signature (IRDS) that predicts resistance to chemotherapy and radiation. The presence of IRDS in African-American tumors was confirmed in another patient cohort and is consistent with other publications that observed overexpression of STAT1 in tumors of African-American patients, a key gene of IRDS. 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 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 project 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) was different in abundance comparing the blood samples from African-American and European-American prostate cancer patients. Currently we are investigating whether the development of this signature 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 suggests 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 and European-American patients. Aberrant expression of subgroup k human endogenous retroviruses (HERV-K) has been previously observed in prostate cancer. This subgroup is unique because it encodes sequences in the human genome containing open reading frames for near intact retroviruses. We hypothesized that HERV-K reactivation could serve as a non-invasive early disease detection marker for prostate cancer. We evaluated HERV-K gag mRNA expression in blood samples of African-American and European-American men using a case-control design via quantitative real-time PCR. Additionally, we examined HERV-K envelope protein expression in prostate tumors by immunohistochemistry. HERV-K envelope protein was commonly up-regulated in prostate tumors, but more so in tumors of African-American than European-American patients (61% versus 40%, P < 0.01). Examining HERV-K gag expression in peripheral blood mononuclear cells (PBMC) from 294 cases and 135 healthy men, we found that the abundance of HERV-K gag message was significantly higher in cases than controls and was |