Background: African American (AA) men exhibit nearly 2-fold higher incidence and 3-fold higher mortality rates from prostate cancer (PC) compared with white men. This disparity likely results from a complex interplay between behavioral, social, neighborhood and biological factors, which all work collectively to generate increased tumor aggressiveness in AAs. Recent data from our laboratory, evaluating human PC biopsy tissue led to the identification of alternative splicing events between AA and white PC that track with increased growth and more aggressive invasion characteristics of PC in AA men. In the present study, we explored associations between genetic variants of 30 such alternatively spliced genes and PC risk, aggressiveness and survival in white and AA groups by analyzing published genome-wide association studies (GWAS) of PC.
Methods: We used GWAS datasets from the Multiethnic Cohort Study of Diet and Cancer (MEC), including AA PC cases and controls, and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), including white PC cases and controls, to evaluate associations of 11,073 and 10,385 single-nucleotide polymorphisms (SNPs), respectively, in 30 genes identified to be alternatively spliced between white and AA PC with PC risk, aggressiveness and survival. For risk, we evaluated 1150 cases and 1101 controls in PLCO and 670 cases and 658 controls in MEC, for aggressiveness, we evaluated 237 aggressive and 843 non-aggressive in PLCO and 234 aggressive and 436 non-aggressive in MEC, and for survival, we evaluated 1150 overall, 237 aggressive and 843 non-aggressive in PLCO. We then performed in silico bioinformatics to investigate potential functions of the SNPs.
Results: Significant associations between SNPs in FN1, COL6A3 and ACACA and SNPs in SEMA3C and FASN and PC risk in white and AA populations, respectively, were identified. In addition, SNPs in ACACA and SNPs in SEMA3C, RELN, MYBPC1, NCOR2 and WDR4 were found to be significantly associated with PC aggressiveness in white and AA populations, respectively. Furthermore, significant associations between SNPs in RHOU, FN1, COL6A3, SEMA3C, RELN, CD44, LMO7 and WDR4 and PC survival in a white population were identified. All of the aforementioned SNPs were predicted to play a role in splicing regulation.
Conclusions: SNPs of race-related alternatively spliced genes that are predicted to play a role in splicing regulation are significantly associated with PC risk, aggressiveness and/or survival in white and/or AA populations. Such variants have the potential to serve as novel molecular targets for development of biomarkers of increased risk of aggressive PC or therapeutics against aggressive PC. Ultimately, such biomarkers and therapeutic agents could serve as novel precision medicine interventions, reducing the mortality burden from PC among AA men.
Citation Format: Jennifer Freedman, Yanru Wang, Hongliang Liu, Patricia Moorman, Terry Hyslop, Daniel George, Norman Lee, Qingyi Wei, Steven Patierno. Single-nucleotide polymorphisms of race-related alternatively spliced genes associate with prostate cancer risk, aggressiveness and/or survival. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B58.