Results from a recent clinical analysis by investigators at the Medical University of South Carolina (MUSC) and the Ralph H. Johnson VA Medical Center (VAMC) have revealed disparities in circulating levels of vitamin D and expression of pro-inflammatory genes, at the transcriptome-level, between African-American (AA) patients with prostate cancer compared to European American (EA) patients. The study—“Systems analysis of the prostate transcriptome in African–American men compared with European–American men”—which was published recently in Pharmacogenomics, revealed that AA men have a significantly higher risk of developing prostate cancer and significantly higher mortality rates than EA men.
Additionally, the researchers found that among patients presenting at the same disease stage, AA men often have more elevated prostate-specific antigen (PSA) levels and higher-grade tumors than EA men. Yet, the biological mechanisms underlying these disparities remain unclear.
"The number of genes expressed differently in AA and EA was a really big surprise—we found differences in over 8,000 genes," remarked co-senior study author Sebastiano Gattoni-Celli, M.D., professor of radiation oncology at MUSC. "I expected something, but not this massive difference, and it was not a fluke. When we compared our results with previous studies using a less advanced technology, we saw that they, too, found these differences, but not as many."
The research team also detected that racial disparities in prostate cancer mirrored differences in circulating levels of vitamin D between AA and EA patients.
"A lot of previous work shows that D3 levels are much lower in African Americans than in European Americans, and it's well established that prostate cells are very sensitive to vitamin D levels,” explained Dr. Gattoni-Celli. “So this raised the possibility that long-term vitamin D deficiency may contribute to the progression of prostate cancer, especially among African American men. We began to wonder whether eliminating racial disparities in circulating levels of vitamin D, through supplementation, could help reduce the disparities we see in prostate cancer outcomes."
The investigators designed a placebo-controlled, clinical study to investigate the effects of a daily 4,000 IU vitamin D3 supplementation over a two-month period among 27 men (10=AA, 17=EA) who had elected to treat their prostate cancer via prostatectomy. The research team used high-throughput RNA sequencing (RNAseq) and performed a series of genome-wide expression profiling experiments to generate transcriptional profiles of patients' prostate tissue samples. Their primary aims were to (1) illuminate any molecular differences in gene expression that may be related to prostate cancer disparities between AA and EA men, and (2) investigate any effects vitamin D supplementation may have on the prostate transcriptome.
The researcher discovered that not only were there significant differences in gene expression between AA and EA men but also between AA men receiving vitamin D supplements and AA men receiving placebo. A total of 3,107 prostate genes were differentially expressed between the AA and EA groups with 8,238 differentially expressed transcripts between AA and EA subjects. Analyses of these found that AA study patients had substantially elevated expression of transcripts related to immune response and inflammation.
"Our findings captured all of the differences observed in previous studies but also many more because newer RNAseq technology and Big Data analytical approaches allowed us to see the transcriptome in greater detail," noted lead study author Gary Hardiman, Ph.D., professor of medicine and public health sciences and bioinformatics director for the Center for Genomic Medicine at MUSC. "This analysis was performed using the OnRamp BioInformatics Genomics Research Platform we deployed at MUSC a little over a year ago. Our approach converged advanced genomics analysis, comprehensive data management, big data analytics and hyperscale servers. A 'Big Data' analytical pipeline that utilized hadoop software was implemented. This enabled an automated RNAseq workflow to process the patient data and explore differential prostate gene expression analysis between AA and EA men and sensitively interrogate the effects of vitamin D supplementation with robust statistical power."