Genetic Variation in the TP53 Pathway and Bladder Cancer Risk. A Comprehensive Analysis

Fondo de Investigacion Sanitaria, Spain [00/0745, PI051436, PI061614, G03/174]; Red Tematica de Investigacion Cooperativa en Cancer, Spain [RD06/0020-RTICC]; Marato TV3 [050830]; European Commission [EU-FP7-HEALTH-F2-2008-201663-UROMOL]; US National InstiPineda, S., Milne, R.L., Calle, M.L., Rothman, N., López De Maturana, E., Herranz, J., Kogevinas, M., Chanock, S.J., Tardón, A., Márquez, M., Guey, L.T., García-Closas, M., Lloreta, J., Baum, E., González-Neira, A., Carrato, A., Navarro, A., Silverman, D.T., Real, F.X., Malats, N

Genome-Wide Association Study of Tanning Phenotype in a Population of European Ancestry

We conducted a multistage genome-wide association study (GWAS) of tanning response after exposure to sunlight in over 9,000 men and women of European ancestry who live in the United States. An initial analysis of 528,173 single-nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified LOC401937 (rs966321) on chromosome 1 as a novel locus highly associated with tanning ability, and we confirmed this association in 870 women controls from a skin cancer case–control study with joint P-value=1.6 × 10−9. We further genotyped this SNP in two subsequent replication studies (one with 3,750 women and the other with 2,405 men). This association was not replicated in either of these two studies. We found that several SNPs reaching the genome-wide significance level are located in or adjacent to the loci previously known as pigmentation genes: MATP, IRF4, TYR, OCA2, and MC1R. Overall, these tanning ability–related loci are similar to the hair color–related loci previously reported in the GWAS of hair color

Analysis of the 10q11 Cancer Risk Locus Implicates MSMB and NCOA4 in Human Prostate Tumorigenesis

Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states

SNPs Meet CNVs in Genome-Wide Association Studies: HGV2007 Meeting Report

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