Presentation Abstract

Abstract Number: 4731
Presentation Title: Resequencing of the MYC-335 enhancer in the colorectal cancer associated 8q24 region
Presentation Time: Tuesday, Apr 20, 2010, 2:00 PM - 5:00 PM
Location: Exhibit Hall A-C, Poster Section 34
Poster Section: 34
Poster Board Number: 15
Author Block: Sari Tuupanen1, Jian Yan1, Mikko Turunen1, Alexandra Gylfe1, Li Li2, Charis Eng3, Daniel Culver4, Matthew Kalady4, Albert de la Chapelle5, Hassan Askhtorab6, Duane Smooth6, Robert Sandler7, Temitope Keku7, Nathan Ellis8, Sonia Kupfer8, Christopher A. Haiman9, Jussi Taipale1, Lauri A. Aaltonen1. 1University of Helsinki, Helsinki, Finland; 2Case Western Reserve University, Cleveland, OH; 3Case Western Reserve University, Cleveland Clinic, Cleveland, OH; 4Cleveland Clinic, Cleveland, OH; 5The Ohio State University, Columbus, OH; 6Howard University College of Medicine, Washington, DC; 7University of North Carolina, Chapel Hill, NC; 8University of Chicago, Chicago, IL; 9University of Southern California, Los Angeles, CA
Abstract Body: Genome-wide association studies have identified multiple different regions at 8q24 associated with risk of colorectal, prostate, breast and bladder cancers. It has been suggested that the cancer predisposition could be mediated through altered MYC expression. One of the regions, marked by SNP rs6983267, has been consistently shown to confer susceptibility to colorectal and prostate cancers. In our previous work, we aimed to understand the biological basis of the colorectal cancer (CRC) predisposition associated with the G allele of rs6983267. By utilizing a computer program, Enhancer Element Locator, we showed that rs6983267 affects a TCF4 binding site in an evolutionary conserved enhancer element (MYC-335). Enhancer activity of this element was confirmed in vitro and in vivo. The G allele of rs6983267 was shown to enhance the activity of the MYC-335, and in the presence of active Wnt signaling potentially lead to increased expression of a target gene, possibly MYC. To examine the contribution of other variants in the MYC-335 to CRC predisposition, we determined the genetic variation within MYC-335 in different ethnic groups by resequencing the 1271-bp genomic fragment in Caucasian, African and African American samples. This effort identified eight variants which showed population-specific allele frequencies. One variant, a 2-bp deletion, affected a putative transcription factor binding site and was present only in individuals with African origin. The deletion affected GA nucleotides at the fifth and sixth position of the putative binding sequence for transcriptional repressor GFI1 (CAGAGATTGC). The identified GFI1 binding sequence is evolutionary highly conserved and the deletion is predicted to cause a 5.5-fold lower binding affinity. Both the SNP rs6983267 and the GA deletion affect transcription factor binding sites and are differentially distributed in different ethnic populations, which suggests that both alleles are functional and under selective pressure from environmental exposure. We hypothesized that the deletion could contribute to CRC predisposition by abolishing the binding of the repressor, which in turn would lead to enhanced transcriptional activity. Here, we show preliminary results that GFI1 has preferential binding affinity for the wild type allele in the heterozygous cell line HeLa. Also, we investigated the role of the deletion in CRC predisposition in African American individuals. The 2-bp deletion identified here might be a novel population-specific colorectal cancer risk variant.