Abstract 4731: Resequencing of the MYC-335 enhancer in the colorectal cancer associated 8q24 region
Authors: Sari Tuupanen, Jian Yan, Mikko Turunen, Alexandra Gylfe, Li Li, Charis Eng, Daniel Culver, Matthew Kalady, Albert de la Chapelle, Hassan Askhtorab, Duane Smooth, Robert Sandler, Temitope Keku, Nathan Ellis, Sonia Kupfer, Christopher A. Haiman, Jussi Taipale, Lauri A. Aaltonen
Journal: Cancer Research (2010)

Abstract 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. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4731.