Abstract
There are striking population disparities in cancer risk and survival outcome borne out of current health statistics. African American (AA) men are approximately 1.6 times more likely to develop prostate cancer (PCa), and 2.4 times more likely to die from this disease compared to their Caucasian American (CA) counterparts. A growing body of biological and genetic evidence suggests that genetic polymorphisms and aberrant gene expression are important influences predisposing or contributing to the disparities of cancer incidence and mortality. Perhaps underappreciated has been the role of alternative splicing in cancer health dis¬parities, and cancer development in general. The expression of specific variants is regulated in a developmentally- and tissue-specific manner. Alternative spliced isoforms from the same gene can pro¬duce proteins with drastically different prop¬erties. We demonstrate that differential alternative splicing takes place for ∼400 genes in PCa specimens of AA compared to CA patients. Many are oncogenes and tumor suppressor genes. In addition, we provide evidence of 4 genes (PIK3CD, FGFR3, TSC2 and RASGRP2) that undergo population-dependent differential splicing where the AA-specific variants are engendered with a more aggressive oncogenic phenotype. Of interest, small molecule inhibitors are clinically available (or being tested clinically) for PIK3CD and FGFR3 in the treatment of various cancers, and we demonstrate in vitro that the AA-specific PIK3CD variant, but not the CA-counterpart, is resistant to small molecule inhibitor CAL-101. Xenograft studies of the splice variants are underway to look at cancer growth, metastasis and response to small molecule inhibitors. Based on our in vitro findings, we hypothesize that the existence of AA-specific splice variants encoding more aggressive oncogenic proteins and/or oncogenic proteins resistant to small molecule inhibitors may account for, in part, the observed cancer health disparities.
Citation Format: Norman Lee. Splice variants associated with African American prostate cancers promote oncogenesis and chemoresistance. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr SS02-01. doi:10.1158/1538-7755.DISP13-SS02-01