Genetic variation in the TP53 pathway and bladder cancer risk. A comprehensive analysis

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

Research output: Contribution to journalArticle

Abstract

Introduction: 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. Material and Methods: 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. Results: 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. Discussion: 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.

Original languageEnglish (US)
Article numbere89952
JournalPLoS One
Volume9
Issue number5
DOIs
StatePublished - May 12 2014
Externally publishedYes

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Urinary Bladder Neoplasms
Single Nucleotide Polymorphism
Tumors
Genes
genetic variation
Regression analysis
operator regions
Mathematical operators
Logistics
Assays
Blood
shrinkage
Association reactions
neoplasms
germ cells
DNA
Testing
Neoplasms
reproducibility
p53 Genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pineda, S., Milne, R. L., Calle, M. L., Rothman, N., López De Maturana, E., Herranz, J., ... Malats, N. (2014). Genetic variation in the TP53 pathway and bladder cancer risk. A comprehensive analysis. PLoS One, 9(5), [e89952]. https://doi.org/10.1371/journal.pone.0089952

Genetic variation in the TP53 pathway and bladder cancer risk. A comprehensive analysis. / Pineda, Silvia; Milne, Roger L.; Calle, M. Luz; Rothman, Nathaniel; López De Maturana, Evangelina; Herranz, Jesús; Kogevinas, Manolis; Chanock, Stephen J.; Tardón, Adonina; Márquez, Mirari; Guey, Lin T.; García-Closas, Montserrat; Lloreta, Josep; Baum, Erin; González-Neira, Anna; Carrato, Alfredo; Navarro, Arcadi; Silverman, Debra T.; Real, Francisco X.; Malats, Núria.

In: PLoS One, Vol. 9, No. 5, e89952, 12.05.2014.

Research output: Contribution to journalArticle

Pineda, S, Milne, RL, Calle, ML, Rothman, N, López De Maturana, E, Herranz, J, Kogevinas, M, Chanock, SJ, Tardón, A, Márquez, M, Guey, LT, García-Closas, M, Lloreta, J, Baum, E, González-Neira, A, Carrato, A, Navarro, A, Silverman, DT, Real, FX & Malats, N 2014, 'Genetic variation in the TP53 pathway and bladder cancer risk. A comprehensive analysis', PLoS One, vol. 9, no. 5, e89952. https://doi.org/10.1371/journal.pone.0089952
Pineda S, Milne RL, Calle ML, Rothman N, López De Maturana E, Herranz J et al. Genetic variation in the TP53 pathway and bladder cancer risk. A comprehensive analysis. PLoS One. 2014 May 12;9(5). e89952. https://doi.org/10.1371/journal.pone.0089952
Pineda, Silvia ; Milne, Roger L. ; Calle, M. Luz ; Rothman, Nathaniel ; López De Maturana, Evangelina ; Herranz, Jesús ; Kogevinas, Manolis ; Chanock, Stephen J. ; Tardón, Adonina ; Márquez, Mirari ; Guey, Lin T. ; García-Closas, Montserrat ; Lloreta, Josep ; Baum, Erin ; González-Neira, Anna ; Carrato, Alfredo ; Navarro, Arcadi ; Silverman, Debra T. ; Real, Francisco X. ; Malats, Núria. / Genetic variation in the TP53 pathway and bladder cancer risk. A comprehensive analysis. In: PLoS One. 2014 ; Vol. 9, No. 5.
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abstract = "Introduction: 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. Material and Methods: 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. Results: 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. Discussion: 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.",
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AU - Pineda, Silvia

AU - Milne, Roger L.

AU - Calle, M. Luz

AU - Rothman, Nathaniel

AU - López De Maturana, Evangelina

AU - Herranz, Jesús

AU - Kogevinas, Manolis

AU - Chanock, Stephen J.

AU - Tardón, Adonina

AU - Márquez, Mirari

AU - Guey, Lin T.

AU - García-Closas, Montserrat

AU - Lloreta, Josep

AU - Baum, Erin

AU - González-Neira, Anna

AU - Carrato, Alfredo

AU - Navarro, Arcadi

AU - Silverman, Debra T.

AU - Real, Francisco X.

AU - Malats, Núria

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N2 - Introduction: 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. Material and Methods: 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. Results: 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. Discussion: 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.

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