Data from <i>FASN</i> Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

• DOI: 10.1158/2767-9764.c.7031724.v1
• Publication Date: 2024-01-18T14:31:48Z
• Authors: Oluwademilade Dairo; Lia DePaula Oliveira; Ethan Schaffer; Thiago Vidotto; Adrianna A. Mendes; Jiayun Lu; Sophie Vo Huynh; 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

<div>Abstract<p>Fatty acid synthase (FASN) catalyzes the synthesis of long-chain saturated fatty acids and is overexpressed during prostatic tumorigenesis, where it is the therapeutic target in several ongoing trials. However, the mechanism of FASN upregulation in prostate cancer remains unclear. Here, we examine <i>FASN</i> gene CpG methylation pattern by InfiniumEPIC profiling and whole-genome bisulfite sequencing across multiple racially diverse primary and metastatic prostate cancer cohorts, comparing with FASN protein expression as measured by digitally quantified IHC assay and reverse phase protein array analysis or <i>FASN</i> gene expression. We demonstrate that the <i>FASN</i> gene body is hypomethylated and overexpressed in primary prostate tumors compared with benign tissue, and <i>FASN</i> gene methylation is significantly inversely correlated with FASN protein or gene expression in both primary and metastatic prostate cancer. Primary prostate tumors with <i>ERG</i> gene rearrangement have increased FASN expression and we find evidence of <i>FASN</i> hypomethylation in this context. FASN expression is also significantly increased in prostate tumors from carriers of the germline <i>HOXB13</i> G84E mutation compared with matched controls, consistent with a report that HOXB13 may contribute to epigenetic regulation of FASN <i>in vitro</i>. However, in contrast to previous studies, we find no significant association of FASN expression or methylation with self-identified race in models that include <i>ERG</i> status across two independent primary tumor cohorts. Taken together, these data support a potential epigenetic mechanism for FASN regulation in the prostate which may be relevant for selecting patients responsive to FASN inhibitors.</p>Significance:<p>Here, we leverage multiple independent primary and metastatic prostate cancer cohorts to demonstrate that <i>FASN</i> gene body methylation is highly inversely correlated with <i>FASN</i> gene and protein expression. This finding may shed light on epigenetic mechanisms of FASN regulation in prostate cancer and provides a potentially useful biomarker for selecting patients in future trials of FASN inhibitors.</p></div>