The Molecular Profile of Prostate Tumors in African-American Men

Division Of Basic Sciences - Nci

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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. Perhaps most unexpected was the presence of an interferon signature in many of the African-American tumors. This signature is closely related to an interferon-related DNA damage resistance signature (IRDS) that predicts resistance to chemotherapy and radiation in breast cancer. IRDS has also been linked to the pro-metastatic epithelial to mesenchymal transition of cancer cells. Thus, IRDS may promote the metastatic process and is, as we found, associated with early disease recurrence in prostate cancer (PMID:30012562). We also observed that aspirin use significantly reduces the risk of aggressive prostate cancer in African American men. Because of this observation, we will now test if the tumor biology of prostate cancer patients who are regular aspirin users is different from patients who do not take aspirin, showing less inflammation. In addition, we examined 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). These observations indicate that patients with the dG allele, which is significantly more common in African than European populations, have an increased occurrence of IRDS. This finding has been published in Clinical Cancer Research (PMID:30012562). 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 study the relationship between viral infection history and the disease using a novel technology, termed VirScan. This technology has recently applied in a study of liver cancer, with our group making key contributions to the analysis of this study (PMID: 32526205). The aim of the prostate cancer study is to examine the viral infection history in men of African descent, and how it relates to prostate cancer, analyzing men from the NCI-Maryland and NCI-Ghana studies and a cohort from Tobago, West Indies. We will also investigate the relationship between the IFNL4 dG genotype and viral infections, and whether there is an interaction between them in prostate cancer development and progression. A completed study linking sexual activity to prostate cancer supports the hypothesis that a viral infection may contribute to the risk of prostate cancer among carriers of the IFNL4 dG genotype (PMID:30456312). An alternative pathway that may lead to an interferon signature in prostate tumors is the aberrant expression of tumor-derived neo-antigens, which can elicit an immune response. For example, it was shown that therapy-induced alterations in DNA methylation can cause the expression of otherwise silenced endogenous retroviral sequences, resulting in an interferon response in tumors and enhanced sensitivity to immune therapy. The observation supports the hypothesis that changes in DNA accessibility can lead to increased neo-antigen presentation, linking DNA accessibility to neo-antigen expression and an immune response. DNA accessibility is largely controlled by the chromatin structure (e.g., open vs. condensed). We hypothesize that distinct chromatin accessibility signatures could be the underlying cause for the increased expression of endogenous retroviral sequences in tumors of African American men and the common occurrence of an interferon signature in them. To test this hypothesis, we will use the Assay for Transposase Accessible Chromatin with high throughput sequencing, termed ATAC-seq, which is a technology for fast and sensitive profiling of chromatin accessibility. Lastly, we are completing work in support of the DoD Impact award, W81XWH1810588 (PI Ambs, Yates, Cook), A Precision Medicine Study of How Inflammation May Underlie the Excessive Burden of Prostate Cancer in Men of African Ancestry. Here, 82 immune-inflammation marker and the fatty acid profile (n=24) of blood samples will be analyzed in NCI-Maryland (see ZIA BC 010499) and NCI-Ghana study participants and will be linked to GWAS and survey data. The aim is to examine associations of these proteins and metabolites with lethal prostate cancer, African ancestry, lifestyle factors, socioeconomic status and neighborhood deprivation index, and medical history. Lastly, we will link these data to tumor biology by studying gene expression profiles and the mutational spectrum (whole exome sequencing) of prostate tumors from the NCI-Maryland study and a cohort from Nigeria (PI Yates). Data from this ongoing project show that circulating chemokines and cytokines related to immune suppression and chemotaxis are generally higher in men of African ancestry (African American and Ghanaian men). When we link the markers to survival, up-regulation of markers that comprise the suppression of tumor immunity pathway robustly associated with lethal prostate cancer in fully adjusted models (manuscript under review). The preventative benefits of aspirin in the development of lethal prostate cancer have been attributed to inhibition of the arachidonic acid signaling pathway. Thromboxane A2 (TXA2), an eicosanoid produced primarily via COX1 in activated platelets, orchestrates platelet aggregation. TXA2, elevated during inflammation, contributes to metastasis. Hence, we assessed the role of TXA2 levels in the development of lethal prostate cancer as part of the DoD Impact Award. Measuring levels of urinary 11-dehydrothromboxane B2 (TXB2), a stable metabolite and marker for TXA2, we observed a distinct elevation of urinary TXB2 in African American men and an inverse association between TXB2 levels and aspirin use. Moreover, high TXB2 was positively associated with metastatic prostate cancer. High TXB2 was also associated with all-cause and prostate cancer-specific mortality in African American men. The data are consistent with our previous findings of a prevalent immune-inflammation signature and an inverse association of aspirin use with lethal prostate cancer in these patients. Our study highlights the potential benefit of aspirin for prevention of lethal prostate cancer in this high-risk group of men through inhibition of TXA2 synthesis. Published in JNCI (PMID: 34264335).