Rare variants in TP53 and susceptibility to neuroblastoma.

Sharon J. Diskin, Mario Capasso, Maura Diamond, Derek A. Oldridge, Karina Conkrite, Kristopher R. Bosse, Mike R. Russell, Achille Iolascon, Hakon Hakonarson, Marcella Devoto, John M. Maris

Research output: Contribution to journalArticle

Abstract

TP53 is the most frequently mutated gene in human malignancies; however, de novo somatic mutations in childhood embryonal cancers such as neuroblastoma are rare. We report on the analysis of three independent case-control cohorts comprising 10290 individuals and demonstrate that rs78378222 and rs35850753, rare germline variants in linkage disequilibrium that map to the 3' untranslated region (UTR) of TP53 and 5' UTR of the Δ133 isoform of TP53, respectively, are robustly associated with neuroblastoma (rs35850753: odds ratio [OR] = 2.7, 95% confidence interval [CI] = 2.0 to 3.6, P combined = 3.43×10(-12); rs78378222: OR = 2.3, 95% CI = 1.8 to 2.9, P combined = 2.03×10(-11)). All statistical tests were two-sided. These findings add neuroblastoma to the complex repertoire of human cancers influenced by the rs78378222 hypomorphic allele, which impairs proper termination and polyadenylation of TP53 transcripts. Future studies using whole-genome sequencing data are likely to reveal additional rare variants with large effect sizes contributing to neuroblastoma tumorigenesis.

Original languageEnglish
JournalJournal of the National Cancer Institute
Volume106
Issue number4
DOIs
Publication statusPublished - 2014

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Neuroblastoma
Odds Ratio
Confidence Intervals
Polyadenylation
Germ Cell and Embryonal Neoplasms
5' Untranslated Regions
Linkage Disequilibrium
3' Untranslated Regions
Neoplasms
Protein Isoforms
Carcinogenesis
Alleles
Genome
Mutation
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Diskin, S. J., Capasso, M., Diamond, M., Oldridge, D. A., Conkrite, K., Bosse, K. R., ... Maris, J. M. (2014). Rare variants in TP53 and susceptibility to neuroblastoma. Journal of the National Cancer Institute, 106(4). https://doi.org/10.1093/jnci/dju047

Rare variants in TP53 and susceptibility to neuroblastoma. / Diskin, Sharon J.; Capasso, Mario; Diamond, Maura; Oldridge, Derek A.; Conkrite, Karina; Bosse, Kristopher R.; Russell, Mike R.; Iolascon, Achille; Hakonarson, Hakon; Devoto, Marcella; Maris, John M.

In: Journal of the National Cancer Institute, Vol. 106, No. 4, 2014.

Research output: Contribution to journalArticle

Diskin, SJ, Capasso, M, Diamond, M, Oldridge, DA, Conkrite, K, Bosse, KR, Russell, MR, Iolascon, A, Hakonarson, H, Devoto, M & Maris, JM 2014, 'Rare variants in TP53 and susceptibility to neuroblastoma.', Journal of the National Cancer Institute, vol. 106, no. 4. https://doi.org/10.1093/jnci/dju047
Diskin SJ, Capasso M, Diamond M, Oldridge DA, Conkrite K, Bosse KR et al. Rare variants in TP53 and susceptibility to neuroblastoma. Journal of the National Cancer Institute. 2014;106(4). https://doi.org/10.1093/jnci/dju047
Diskin, Sharon J. ; Capasso, Mario ; Diamond, Maura ; Oldridge, Derek A. ; Conkrite, Karina ; Bosse, Kristopher R. ; Russell, Mike R. ; Iolascon, Achille ; Hakonarson, Hakon ; Devoto, Marcella ; Maris, John M. / Rare variants in TP53 and susceptibility to neuroblastoma. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 4.
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