Journal Article

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

García-Closas, Montserrat, Calle, M. Luz, Márquez, Mirari, Silverman, Debra T., Real, Francisco X., Lloreta, Josep, Pineda, Silvia, Kogevinas, Manolis, Herranz, Jesús, Tardón, Adonina, Navarro, Arcadi, Milne, Roger L., Chanock, Stephen J., González-Neira, Anna, Carrato, Alfredo, López de Maturana, Evangelina, Baum, Erin, Rothman, Nathaniel, Guey, Lin T., Malats, Núria

2014

Overview

Germline variants in TP63 have been consistently associated with several tumors, including bladder cancer, indicating the importance of TP53 pathway in cancer genetic susceptibility. However, variants in other related genes, including TP53 rs1042522 (Arg72Pro), still present controversial results. We carried out an in depth assessment of associations between common germline variants in the TP53 pathway and bladder cancer risk. We investigated 184 tagSNPs from 18 genes in 1,058 cases and 1,138 controls from the Spanish Bladder Cancer/EPICURO Study. Cases were newly-diagnosed bladder cancer patients during 1998-2001. Hospital controls were age-gender, and area matched to cases. SNPs were genotyped in blood DNA using Illumina Golden Gate and TaqMan assays. Cases were subphenotyped according to stage/grade and tumor p53 expression. We applied classical tests to assess individual SNP associations and the Least Absolute Shrinkage and Selection Operator (LASSO)-penalized logistic regression analysis to assess multiple SNPs simultaneously. Based on classical analyses, SNPs in BAK1 (1), IGF1R (5), P53AIP1 (1), PMAIP1 (2), SERINPB5 (3), TP63 (3), and TP73 (1) showed significant associations at p-value≤0.05. However, no evidence of association, either with overall risk or with specific disease subtypes, was observed after correction for multiple testing (p-value≥0.8). LASSO selected the SNP rs6567355 in SERPINB5 with 83% of reproducibility. This SNP provided an OR = 1.21, 95%CI 1.05-1.38, p-value = 0.006, and a corrected p-value = 0.5 when controlling for over-estimation. We found no strong evidence that common variants in the TP53 pathway are associated with bladder cancer susceptibility. Our study suggests that it is unlikely that TP53 Arg72Pro is implicated in the UCB in white Europeans. SERPINB5 and TP63 variation deserve further exploration in extended studies.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Aged, 80 and over / Bioinformatics / Biology and Life Sciences / Bladder / Bladder cancer / Breast cancer / Cancer / Cell cycle / Deoxyribonucleic acid / DNA / Epidemiology / Female / Genes / Genetic aspects / Genetic diversity / Genetic Predisposition to Disease - genetics / Genetic research / Genetic Variation - genetics / Genetics / Genetics & genetic processes / Genomes / Genotype / Génétique & processus génétiques / Haplotypes / Health aspects / Health risk assessment / Health risks / Hospitals / Humans / Life sciences / Male / Medical prognosis / Medical research / Medicine and Health Sciences / Middle Aged / Morphology / Mutation / p53 Protein / Physical Sciences / Polymorphism, Single Nucleotide - genetics / Regression analysis / Reproducibility / Risk analysis / Risk assessment / Risk factors / Sciences du vivant / Shrinkage / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Studies / Tumor proteins / Tumor Suppressor Protein p53 - genetics / Tumors / Urinary bladder / Urinary Bladder Neoplasms - genetics / Young Adult