Evaluation of Allele-Specific Somatic Changes of Genome-Wide Association Study Susceptibility Alleles in Human Colorectal Cancers Madelyn M. Gerber 1 , Heather Hampel 2,3,4 , Nathan P. Schulz 2 , Soledad Fernandez 5 , Lai Wei 5 , Xiao- Ping Zhou 6 , Albert de la Chapelle 3,4,7 , Amanda Ewart Toland 3,4,7 * 1 Integrated Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, United States of America, 2 The Ohio State University College of Medicine, Columbus, Ohio, United States of America, 3 Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America, 4 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America, 5 The Center for Biostatistics, The Ohio State University, Columbus, Ohio, United States of America, 6 Department of Pathology, The Ohio State University, Columbus, Ohio, United States of America, 7 Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America Abstract Background: Tumors frequently exhibit loss of tumor suppressor genes or allelic gains of activated oncogenes. A significant proportion of cancer susceptibility loci in the mouse show somatic losses or gains consistent with the presence of a tumor susceptibility or resistance allele. Thus, allele-specific somatic gains or losses at loci may demarcate the presence of resistance or susceptibility alleles. The goal of this study was to determine if previously mapped susceptibility loci for colorectal cancer show evidence of allele-specific somatic events in colon tumors. Methods: We performed quantitative genotyping of 16 single nucleotide polymorphisms (SNPs) showing statistically significant association with colorectal cancer in published genome-wide association studies (GWAS). We genotyped 194 paired normal and colorectal tumor DNA samples and 296 paired validation samples to investigate these SNPs for allele- specific somatic gains and losses. We combined analysis of our data with published data for seven of these SNPs. Results: No statistically significant evidence for allele-specific somatic selection was observed for the tested polymorphisms in the discovery set. The rs6983267 variant, which has shown preferential loss of the non-risk T allele and relative gain of the risk G allele in previous studies, favored relative gain of the G allele in the combined discovery and validation samples (corrected p-value = 0.03). When we combined our data with published allele-specific imbalance data for this SNP, the G allele of rs6983267 showed statistically significant evidence of relative retention (p-value = 2.06 6 10 24 ). Conclusions: Our results suggest that the majority of variants identified as colon cancer susceptibility alleles through GWAS do not exhibit somatic allele-specific imbalance in colon tumors. Our data confirm previously published results showing allele-specific imbalance for rs6983267. These results indicate that allele-specific imbalance of cancer susceptibility alleles may not be a common phenomenon in colon cancer. Citation: Gerber MM, Hampel H, Schulz NP, Fernandez S, Wei L, et al. (2012) Evaluation of Allele-Specific Somatic Changes of Genome-Wide Association Study Susceptibility Alleles in Human Colorectal Cancers. PLoS ONE 7(5): e37672. doi:10.1371/journal.pone.0037672 Editor: Ludmila Prokunina-Olsson, National Cancer Institute, National Institutes of Health, United States of America Received January 17, 2012; Accepted April 26, 2012; Published May 21, 2012 Copyright: ß 2012 Gerber et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was funded in part by the NIH/NCI (CA134461 to AET and CA67941 to AdlC) and the Ohio State University Comprehensive Cancer Center Core grant (CA16058). MMG was funded by an OSU College of Medicine Systems and Integrated Biology training grant. NPS was funded by an OSU College of Medicine Medical Student Research Scholarship. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Competing Interests: Amanda Toland is a PLoS ONE Editorial Board member. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: Amanda.Toland@osumc.edu Introduction Tumor suppressor genes and oncogenes have long been recognized to show copy number losses and gains in tumors, respectively [1,2]. Classically, the wild-type allele of tumor suppressor genes is lost in tumors whereas the mutated or non- functional allele shows selective retention. Likewise, an activated mutation or activated copy of an oncogene is frequently selected for gain or amplification in tumors. Previous studies using mouse models show evidence that a subset of susceptibility loci for skin and colon cancer demonstrate strain-specific gains or losses consistent with these loci housing tumor promoting alleles or tumor suppressing alleles [3,4]. For example, PTPRJ, a gene originally identified as a candidate tumor suppressor mapping to the mouse Scc1 locus, was shown to preferentially lose a suspected resistance allele in a subset of heterozygous human colorectal adenocarcinomas showing loss of heterozygosity at PTPRJ [3]. Allele-specific gains of a single nucleotide polymorphism (SNP) in AURKA, rs2273535, have been observed in multiple studies of colorectal tumors [5,6]. Preferential allelic gains or losses in PLoS ONE | www.plosone.org 1 May 2012 | Volume 7 | Issue 5 | e37672