Abstract #1342: Loss of FHIT expression due to epigenetic silencing is a frequent event in African American (AA) patients with colorectal cancer (CRC)

Introduction: CRC incidence and mortality are higher in AA patients compared to Caucasians, and colorectal polyps develop at younger ages in AA patients. Prior studies have failed to identify genetic markers that account for the poorer CRC prognosis in AA with CRC. We hypothesized that aberrant epigenetic silencing of tumor suppressor genes (TSG), perhaps influenced by dietary and lifestyle factors, may provide an explanation for this. Aim: We compared gene expression profiles in CRC tissues from AA and Caucasian patients to identify potential epigenetic TSG targets in AA patients. Methods: Samples were drawn from 486 CRC patients (218 AA and 286 Caucasians) enrolled in the population-based North Carolina Colon Cancer Study (NCCCS). Microarray-based gene expression profiling of ~45,000 mRNA transcripts was performed on a subset of 42 patients (19 AA and 23 Caucasian) from whom fresh frozen tissue was available. Data were analyzed using SAM, Cluster, TreeView and hierarchical clustering algorithms to identify significantly down-regulated genes in AA vs Caucasian subjects. Microsatellite instability (MSI) was determined using 5 mononucleotide markers. Methylation-specific PCR (MSP) and bisulfite sequencing analyses were used to analyze promoter methylation. Results: Gene expression analysis identified a subset of 94 genes that were significantly under-expressed in AA patients compared to Caucasians, including fragile histidine triad (FHIT), claudin 3 (CLDN3), BRCA1 associated protein 1 (BAP1), CDK1 associated protein 2 (CDK1AP2) and nuclear transcription factor Y-alpha (NFYA), all of which are TSG targets of methylation-induced silencing in various human cancers. MSP analysis of the FHIT promoter in a randomly selected subset of 126 CRCs (61 AA and 65 Caucasian) revealed a significantly higher frequency of FHIT methylation in AA compared to Caucasian subjects (39% vs 22%; P Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1342.