Fatty Acid Synthase in the Endoscopically Normal Rectal Mucosa as Marker for Obesity-related Colorectal Cancer (CRC) Risk: Gender-specific Implications: Presidential Poster

Abstract

Purpose: The clinical implications of the profound biological differences in CRC between women and men are largely underappreciated. Our group has noted a “gender paradox” for advanced adenomas and CRC in women and men which may have potential ramifications for screening (JAMA 2009;302:1696-7). We have noted that changes in field carcinogenesis (reviewed in Gastroenterology 2011;140:35-41) may also be gender specific (Cancer Prev Res 2010;3:844-51). With regards to risk factor, the role of obesity is becoming increasingly dominant. Emerging data indicates that men appear to be disproportionately impacted versus women (reviewed by Bardou, et al. Gut 2013;62:933-47). Understanding which obese patients are at elevated risk of CRC is critical. We, therefore, evaluated fatty acid synthase (FASN), a protein implicated in the “lipogenic switch” in early colon carcinogenesis. FASN has been implicated in frank CRCs but little is known about the role of FASN in early events such as field carcinogenesis or its gender predilection. Methods: Two biopsies were obtained from endoscopically normal rectum from 103 patients undergoing screening colonoscopy. Subjects were dichotomized into non-obese and obese using a BMI of 30 as a cut point. Biopsies were subjected to real time PCR analysis for FASN and normalized with beta-actin. Results: Obese patients had an induction of FASN when compared to corresponding non-obese subjects (controls 50%, adenoma-harboring 29%, p<0.05). Rectal FASN was highly overexpressed in adenoma patients versus controls and this was a much more dramatic effect in men than women (see Figure). ANCOVA analysis suggested no significant confounding with age, adenoma size, smoking status, etc.FigureConclusion: We report herein, for the first time, alterations in FASN in patients harboring adenomas. This was accentuated in obese patients suggesting a potential molecular link between obesity and colonic neoplasia. Importantly, the effect was more marked in males than females, consonant with the obesity-CRC epidemiology. These insights into the molecular pathogenesis of obesity-related CRC suggest a role of this “lipogenic switch” in gender differences in CRC. Furthermore, this may be a “druggable” target against obesity-induced CRC and also provide a biomarker for determining at risk patients, thus enabling personalizing CRC prevention strategies.