Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable

Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including and single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1. In the USA, testicular germ cell tumors (TGCT [MIM 273300]) are the most common cancers in young men, with a peak incidence among those aged 25C34 years. The incidence of TGCT among white men in the USA has increased substantially over the past 30 years from 4.1 per 100 000 in 1975 to 7.0 per 100 000 in 2007 (1), and similar increases are seen worldwide (2). The disease incidence varies widely across racial groups, with a 5-fold lower rate among black men in the USA (1). Differences in incidence of TGCT also exist across countries and continents, ranging from Denmark (9.2 per 100 000) to Algeria (0.2 per 100 000), which is consistent with racial differences and lower rates in nonwhite groups (3). Familial aggregation of TGCT has been documented since the 1930s, SGI-1776 and family history is the strongest known risk factor for these malignancies (4,5). Risk of TGCT repeatedly has been shown to be increased among first-degree relatives of affected men, with risk to brothers (estimates range from 5- to 19-fold) being stronger than that to fathers (estimates range from 2- to 4-fold) (6C14). Both mono- and dizygotic twins of affected men have increased risk of TGCT (15,16). Genetic effects have been estimated to account for 25% of TGCT, the third highest heritability among all cancers (17). These familial data along with the racial disparity in disease occurrence provide evidence of a genetic contribution to TGCT susceptibility. Supporting the genetic contribution to TGCT susceptibility, initial findings from genome-wide association (GWA) studies implicate variation at the and as associated with TGCT susceptibility (18,19). Prior to these publications, no common susceptibility alleles had been validated. More recently, a follow-up GWA study from the UK also identified and replicated variation in and as associated with TGCT (20). Herein, we report the results from our follow-up GWA study in the USA, for which we augmented the number of TGCT cases used in the discovery sample as well as TGCT cases and controls used in the replication sample in order to identify additional TGCT susceptibility loci and to validate the new findings. RESULTS Information on age, risk factors and tumor characteristics for the discovery and replication sample sets are given in Table?1. The calculated genomic control inflation () factor in the discovery set was 0.942, and hence we report unadjusted test statistics (21,22). We again noted our previously reported statistically SGI-1776 significant associations with markers at 12q22 in (< 5.0 10?8), 2p14 and 5q13.3 near (< 5.0 10?6; Fig.?1 and Supplementary Material, Table S1) (18). Six additional markers at five additional autosomal loci SGI-1776 also were associated with TGCT (< 5.0 10?6). To screen out hits representing likely false positive associations, we imputed genotypes in the surrounding regions of these six markers using data from 1000 genomes (March 2010 release) (Fig.?2A and Supplementary Material, Fig. S1). After imputation, neither observed nor imputed markers at 8q21.3 and 13q12.3 maintained significance at < 5 10?6 and were excluded from Mouse monoclonal to Cytokeratin 8 further study, whereas markers at 4q28.2, 7q21.13 and 9p24.3 continued to exceed the < 5 10?6 threshold. The selected markers on chromosomes 4 and 7 that were brought forward into replication included two imputed (rs2279070, rs4834214) that SGI-1776 mapped to 4q28.2, as the observed single nucleotide polymorphism (SNP) could not be designed SGI-1776 for replication genotyping, and two observed (rs6951213, rs10281060) that mapped within introns 1 and 2 of on 7q21.13. For chromosome 9 markers, the top three imputed markers using 1000 genomes were incompatible with our replication genotyping platform, so we re-imputed markers in this region using data from HapMap (release 22). The top imputed marker (rs755383), which was previously showed to be associated with TGCT by Turnbull < 5 10?6 threshold (Supplementary Material, Fig. S2). Table?1. Age, family history of TGCT and tumor type in the discovery and replication sample sets Figure?1. Manhattan plot of GWA results for 349 TGCT cases and 919 controls. SNP markers that reached.

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