Colorectal cancer (CRC) represents a serious public health problem that affects African Americans (AA) disproportionately. Both incidence rates and morbidity and mortality is higher in AAs than in other Americans. Family history, that is, genetic risk, remains one of the most important factors in recommendations for screening. Recent genome-wide association studies have identified 10 independent regions harboring genetic risk factors in CRC in populations of European ancestry. Using single-nucleotide polymorphisms (SNPs) from these studies, we have obtained evidence of association in four of these regions in AA CRC. Our goal is to identify the functional genetic risk factors, quantify their effects, and determine their functions. To pursue this goal, we propose four Aims. (1) We will validate previously identified candidate CRC-associated regions in AA CRC cases and controls. We will use Sequenom genotyping and tag SNPs from these regions to identify SNPs associated with CRC in AAs. We will use 100 ancestry informative markers to perform a structured logistic regression analysis that takes into account possible population stratification based on ancestry. Because AAs are more diverse than European Americans, these studies will very likely lead to better localization of the genetic risk factors. (2) We will use Next Generation Sequencing (NGS) technology to conduct a resequencing analysis of each candidate genetic region in 96 (48 CRC and 48 controls) persons with CRC. The region that we resequence will be guided by the genes and linkage disequilibrium observed in each CRC-associated region. (3) We will better quantify the effects of the genetic risk factors in each region. We will perform a bioinformatics analysis to identify putative functional variants. These functional candidates along with our novel genetic variants in CRC-associated regions will be genotyped in up to 2000 AA cases and 2000 AA control. We will perform structured logistic regression analysis to obtain the strongest genotype relative risks in each CRC-associated regions. (4) The foregoing analyses will provide a short-list of candidate genetic risk factors for each CRC-associated region. We will begin to characterize the molecular basis of CRC risk for each region by functional assays designed based on the putative mechanism caused by the genetic variants (regulatory or enzymatic). Molecular assays (for example, luciferase reporter assays) will be designed to determine the functional impact of candidate genetic risk factors.
Colorectal cancer affects African Americans disproportionately relative to other Americans. The discovery of genetic risk factors associated with colorectal cancer predisposition is tantamount to a fundamental understanding of the etiology of this significant health problem and to recommendations for cancer screening. We have found several candidate regions that contain genetic risk factors in African Americans. These and other regions have been implicated in colorectal cancer risk by validated genetic associations. We will determine the functional genetic variants that increase risk by genetic and functional studies. These studies will have important implications for early detection and possibly therapeutic intervention among African Americans.
|Hulur, Imge; Gamazon, Eric R; Skol, Andrew D et al. (2015) Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci. BMC Genomics 16:138|
|Pibiri, Fabio; Kittles, Rick A; Sandler, Robert S et al. (2014) Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans. Cancer Causes Control 25:561-70|
|Kupfer, Sonia S; Skol, Andrew D; Hong, Ellie et al. (2014) Shared and independent colorectal cancer risk alleles in TGFÎ²-related genes in African and European Americans. Carcinogenesis 35:2025-30|
|Xicola, Rosa M; Gagnon, Molly; Clark, Julia R et al. (2014) Excess of proximal microsatellite-stable colorectal cancer in African Americans from a multiethnic study. Clin Cancer Res 20:4962-70|
|Ellis, Nathan A; Offit, Kenneth (2012) Heterozygous mutations in DNA repair genes and hereditary breast cancer: a question of power. PLoS Genet 8:e1003008|
|Tuupanen, Sari; Yan, Jian; Turunen, Mikko et al. (2012) Characterization of the colorectal cancer-associated enhancer MYC-335 at 8q24: the role of rs67491583. Cancer Genet 205:25-33|
|Kupfer, Sonia S; Anderson, Jeffrey R; Ludvik, Anton E et al. (2011) Genetic associations in the vitamin D receptor and colorectal cancer in African Americans and Caucasians. PLoS One 6:e26123|
|Theodoratou, E; Campbell, H; Tenesa, A et al. (2010) A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer 103:1875-84|
|Kupfer, Sonia S; Anderson, Jeffrey R; Hooker, Stanley et al. (2010) Genetic heterogeneity in colorectal cancer associations between African and European americans. Gastroenterology 139:1677-85, 1685.e1-8|