Discordant Regulation of Colonic Mucosal Fatty Acid Synthase (FASN) in African Americans and Caucasians: Implications for Colorectal Cancer Disparities

Abstract

Introduction: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortalities in Americans. As compared to racial cancer disparities, it ranks as one of the most significant with a 23% and 53% increase in incidence and mortality, respectively in African Americans versus Caucasians. However, the etiology of this is unclear. Since ˜70% of CRC risk is believed to be exogenous (especially the doubling of risk with either diabetes or obesity), this represents a potential candidate. Indeed, African Americans have a 50% greater incidence of both diabetes and obesity. Furthermore, there is epidemiological data to suggest that African Ameicans are more sensitive to the pro-colon neoplastic effects, though the molecular mediators are yet to be fully elucidated. Our research group has focused on field carcinogenesis to detect risk of concurrent and future neoplasia (Gastro 2011, Clin Gastro Hep 2012). We have recently reported that one of the earliest events is the alteration in colonic epithelial metabolism; fatty acid synthase (FASN) appears critical in this “lipogenic switch” (changing from fatty acid consumption to production for synthesizing lipid membranes) and has in a variety of obesity-related cancers (e.g., prostate, breast). However, the role of FASN in racial disparities has not been explored. Methods: To explore the expression of FASN in CRC field carcinogenesis, patients (n=54) undergoing screening colonoscopy had 2 biopsies obtained from endoscopically normal rectal mucosa. Following homogenization and RNA quantification (Nanodrop), RNA was isolated to assess FASN levels through real-time PCR with β-actin used as an internal control. Results: Real-time PCR displayed marked differences in FASN expression. African Americans controls (no adenomas) showed a 1.72-fold higher basal level FASN expression as compared to Caucasians. With regards to field carcinogenesis, Caucasians harboring neoplasia had a 96% increase in FASN expression whereas African Americans with neoplasias showed a 50% decrease (as compared to their respected controls). Conclusion: We demonstrate, for the first time, that FASN was differentially regulated in African Americans when compared to Caucasians during colon carcinogenesis. The suppression of FASN is intriguing and may suggest more aggressive behavior of malignancy consistent with recent data from the Nurses Health Study (JNCI 2012). FASN may serve as an important biomarker for disparity-induced cancer for both personalizing screening (understanding which African American patients are at highest risk) and also as a potential therapeutic target.