Abstract C054: Association of fatty acid synthase expression with FASN gene methylation and self-identified race in prostate cancer

Abstract

Abstract Fatty acid synthase (FASN) catalyzes the synthesis of long-chain saturated fatty acids and is overexpressed during prostatic tumorigenesis; however, the mechanism of this upregulation remains unclear and could include gene amplification, epigenetic regulation or regulation by androgen receptor (AR). Though FASN is an attractive therapeutic target in prostate cancer and several clinical trials of FASN inhibitors are underway, prior studies have suggested racial disparities in FASN copy number and FASN protein expression exist in primary prostate cancer, which may have implications for the therapeutic efficacy of FASN inhibitors. FASN gene amplification may be more common in prostate cancers from self-identified Black (BL) patients than their White (WH) counterparts, and a recent study has suggested that FASN protein expression is also higher among primary prostate tumors from BL compared to WH men due to changes in the AR cistrome. Here, we examine FASN protein expression as measured by digitally quantified immunohistochemistry assay and reverse phase protein array analysis or FASN gene expression, comparing it to gene CpG methylation pattern by InfiniumEPIC profiling and whole genome bisulfite sequencing (WGBS) across multiple racially diverse primary and metastatic prostate cancer cohorts, including more than 1000 tumors. We demonstrate that the FASN gene body is hypomethylated and overexpressed in primary prostate tumors compared to benign tissue. FASN gene methylation shows a significant inverse correlation with FASN protein and gene expression in both primary and metastatic prostate cancer. However, in contrast to previous studies, we find no significant association of FASN expression or methylation with self-identified race or genetic ancestry in models that include ERG gene fusion status across two independent primary tumor cohorts. Taken together, these data support a potential epigenetic mechanism for FASN regulation in the prostate and suggest that FASN inhibitors may be equally efficacious in both BL and WH men with prostate cancer. Citation Format: Oluwademilade Dairo, Lia DePaula Oliveira, Ethan Schaffer, Thiago Vidotto, Adrianna Amaral De Aragao Mendes, Jiayun Lu, Jessica Hicks, Adam G. Sowalsky, Angelo M. De Marzo, Corrine E. Joshu, Brian Hanratty, Karen S. Sfanos, William B. Isaacs, Michael C. Haffner, Tamara L. Lotan. Association of fatty acid synthase expression with FASN gene methylation and self-identified race in prostate cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C054.