Genetic variants located within the 12p13. Upper aerodigestive tract (UADT) cancers comprising of the oral cavity larynx and esophagus are the fourth most common cause of cancer death worldwide . While consumption of tobacco and alcohol are the main UADT cancers risk factors  genetic susceptibility has been hypothesized to play a role in the pathogenesis of this disease [3 4 Exposure to tobacco and alcohol leads to cell damage and DNA alterations that in the absence of appropriate repair may cause cell cycle deregulation and cancer development [5 6 Homologous Recombination (HR) is an important manner by which cells repair DNA lesions [7 8 The gene is usually involved in the homologous recombination DNA repair process  by mediating RAD51 a central HR gene that forms a helical nucleoprotein filament involved in the search for homology and strand pairing . Genome wide Rabbit Polyclonal to FGFR1. association studies (GWAS) have implicated the rs10849605 genetic variant at 12p13.33 the locus that encompasses in the human genome to be associated with a modest but statistically significant increased risk of lung cancer [11 12 It appears most relevant to lung squamous cell carcinoma (LUSC) and small cell lung cancers but with little evidence within lung adenocarcinomas (LUAD) [11 12 Although the molecular mechanisms contributing to initiation and progression are still poorly understood squamous cell carcinomas (SCC) of different anatomical sites share many phenotypic and molecular characteristics with each other . The aim of the present study was to investigate in the context of genetic susceptibility to SCC of the UADT to explore how this association might be mediated and examine the somatic mutation events at the 12p13.33 locus. Materials and Methods Study subjects A total of 9 case-control studies of UADT cancer participated in our present study totalling 5 947 UADT cancer cases and 7 789 controls. Study designs and population characteristics have been described in more details previously [3 14 15 and are briefly described in Table 4-HQN 1. In most studies the 4-HQN control subjects were frequency matched to the cases on age sex and additional factors (e.g. study site and hospital). Written informed consent was obtained from all study subjects and the investigations were approved by the institutional review boards at each study center. Analysis was restricted to squamous cell carcinomas. Table 1 Demographic characteristics of the cases and controls included in the genetic susceptibility study of and was not covered by exome sequencing. Therefore we derived the genotypes for 263 HNSC 223 LUSC and 125 LUAD individuals using the Affymetrix 6.0 SNP array TCGA data. Statistical methods Association analysis The association between the variants and UADT cancer risk was 4-HQN estimated by odds ratio (ORs) and 95% confidence intervals (CIs) per allele under the log-additive model and genotype derived from multivariate unconditional logistic regression with sex and study specific country of origin included in the model as covariates (S1 Table). Heterogeneity of ORs was assessed using the Cochran’s Q test. Statistical analyses were performed using SAS version 9.3 (SAS Institute Cary NC USA). To control for potential ethnic heterogeneity between cases and controls we performed a principal components analysis using the EIGENSTRAT package of the EIGENSOFT 5.0 software  using 12 898 markers in low linkage disequilibrium . We 4-HQN used the resulting 12 statistically significant eigen vectors (as defined by the Tracy-Widom statistics) in the sensitivity analysis (Table A in S1 File). eQTL analyses The association between rs10849605 germline genotype and tumor expression levels (eQTL) was tested on 263 HNSC 223 LUSC and 125 LUAD using a linear model. It has been repeatedly observed that tumors acquire somatic alterations that can also influence gene expression particularly copy number changes and DNA methylation [22-24]. Therefore we tested the eQTL effect of rs10849605 on tumor expression using both adjusted and non-adjusted.