miRNA-Related Polygenic Risk Score and miRNA Expression on Prostate Cancer Survival in Whites and Blacks
Abstract
One out of seven American men will develop prostate cancer (PCa) during their lifetime. PCa is the second leading cause of cancer-related deaths in American men and has substantial clinical heterogeneity. The 5-year survival rate for PCa patients with the distant stage is only 31%, although the rate for overall PCa patients is 99%. At the time of diagnosis, physicians often have difficulty distinguishing between patients who will develop indolent tumors and those who will develop aggressive tumors. In addition, health inequities of PCa incidence and progression have been observed between Whites and Blacks. Blacks suffer a 60% higher PCa incidence rate and 2.2 times higher mortality rate than Whites. Although the racial disparity between Whites and Blacks remains for decades, the determinants of this high rate of incidence, aggression, and mortality in Blacks are still unknown. The existing clinical features (such as clinical stage and Gleason score) are useful but insufficient for classifying high- and low-risk PCa patients. With this inadequate risk classification, approximately 20% of low-risk PCa patients died due to conservative treatment, and many PCa patients suffered side effects of overtreatments. Thus, there is an urgent need to identify additional biomarkers to improve the prediction accuracy of lethal PCa. Most current genetic association studies focus on evaluating individual effects of single nucleotide polymorphisms (SNPs), inherited genetic variants, which are insufficient to explain the complexity of disease causality. The objective of this study is to identify tumor miRNA expression and related SNP-SNP interaction pairs and build polygenic risk scores (PRS) for predicting PCa survival by searching for the miRNA genes for Whites and Blacks. miRNAs regulate 30-60% of human genes and are considered essential components of gene regulatory networks. Our published study supported that several SNPs located in a miRNA binding site can predict PCa aggressiveness. In Aim 1, we will identify a set of miRNA expression associated with both PCa survival/aggressiveness and SNP-SNP interaction pairs or SNPs in the KLK3 SNP-interaction network and the SNPs identified in genome-wide association studies. We will perform tumor miRNA expression for the ~850 PCa cases (including 308 Blacks). In Aim 2, we will evaluate SNP-SNP interaction pairs in this candidate gene set associated with PCa-specific survival/aggressiveness using the novel and powerful statistical methods proposed by our research team. In Aim 3, we will develop race-specific PRS systems and compare their performance with PCa clinical features such as PSA, tumor stage, and Gleason score. For Aims 2 and 3, the large-scale PCa consortium, a collection of 37,303 White and 4,888 Black PCa patients, will be applied. Our study can make a great impact because it has many strengths. The biological mechanisms of lethal PCa may differ for race groups. To address this issue, this study will develop these risk classifiers of PCa survival/aggressiveness for Whites and Blacks separately. By doing so, better prediction of PCa survival can be achieved for each race group, so these race-specific risk classifiers based on SNPs and miRNA expression profiles can potentially reduce PCa progression and death overall and reduce disparities in PCa. In addition, this study will use data from the largest PCa consortium globally, and both Whites and Blacks will be evaluated. A majority of current studies focused on white men only. The findings will be based on solid validation for both SNP-SNP pairs and miRNA-based PRS associated with PCa survival/aggressiveness. This design will reduce false-positive findings and make results more generalizable to other PCa patients. In addition, powerful and novel statistical methods will be used for SNP-SNP interactions and miRNA expression analyses. The identified PRS systems can predict future lethal PCa development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310438
Entities
People
- Hui-Yi Lin
Organizations
- LSU Health Sciences Center New Orleans
- United States Army