Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Apr;106(4):dju047.
doi: 10.1093/jnci/dju047. Epub 2014 Mar 14.

Rare Variants in TP53 and Susceptibility to Neuroblastoma

Free PMC article

Rare Variants in TP53 and Susceptibility to Neuroblastoma

Sharon J Diskin et al. J Natl Cancer Inst. .
Free PMC article


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.


Figure 1.
Figure 1.
Discovery of rare variants within TP53 associated with neuroblastoma. A) Regional association plot of genotyped and imputed single nucleotide polymorphisms (SNPs) at the TP53 locus in a discovery cohort of 2101 case patients and 4202 control subjects of European ancestry. Plot was generated using LocusZoom (25). Y-axes represent the statistical significance of association (-log10 transformed P values) and the recombination rate. SNPs are color-coded based on pair-wise linkage disequilibrium (r 2) with most statistically significant SNP. Most statistically significant SNPs are labeled with P value, and most statistically significant SNP is shown in purple. Allelic P values generated by SNPTEST using score method (two-sided). B) Neuroblastoma-associated SNPs map to the 3΄ untranslated region (UTR) of TP53 and 5΄ UTR of the Δ133 isoform of TP53, respectively. The Δ133 isoform is transcribed by an alternative promoter (P2) and lacks a transactivation domain and part of the DNA binding domain. Shown are known isoforms of TP53 currently reported in the NCBI Reference Sequence database (RefSeq). BD = basic domain; DBD = DNA binding domain; OD = oligomerization domain; TAD = transactivation domain.

Similar articles

  • A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
    Stacey SN, Sulem P, Jonasdottir A, Masson G, Gudmundsson J, Gudbjartsson DF, Magnusson OT, Gudjonsson SA, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Nexø BA, Tjønneland A, Overvad K, Rudnai P, Gurzau E, Koppova K, Hemminki K, Corredera C, Fuentelsaz V, Grasa P, Navarrete S, Fuertes F, García-Prats MD, Sanambrosio E, Panadero A, De Juan A, Garcia A, Rivera F, Planelles D, Soriano V, Requena C, Aben KK, van Rossum MM, Cremers RG, van Oort IM, van Spronsen DJ, Schalken JA, Peters WH, Helfand BT, Donovan JL, Hamdy FC, Badescu D, Codreanu O, Jinga M, Csiki IE, Constantinescu V, Badea P, Mates IN, Dinu DE, Constantin A, Mates D, Kristjansdottir S, Agnarsson BA, Jonsson E, Barkardottir RB, Einarsson GV, Sigurdsson F, Moller PH, Stefansson T, Valdimarsson T, Johannsson OT, Sigurdsson H, Jonsson T, Jonasson JG, Tryggvadottir L, Rice T, Hansen HM, Xiao Y, Lachance DH, O Neill BP, Kosel ML, Decker PA, Thorleifsson G, Johannsdottir H, Helgadottir HT, Sigurdsson A, Steinthorsdottir V, Lindblom A; Swedish Low-risk Colorectal Cancer Study Group, Sandler RS, Keku TO, Banasik K, Jørgensen T, Witte DR, Hansen T, Pedersen O, Jinga V, Neal DE, Catalona WJ, Wrensch M, Wiencke J, Jenkins RB, Nagore E, Vogel U, Kiemeney LA, Kumar R, Mayordomo JI, Olafsson JH, Kong A, Thorsteinsdottir U, Rafnar T, Stefansson K. Stacey SN, et al. Nat Genet. 2011 Sep 25;43(11):1098-103. doi: 10.1038/ng.926. Nat Genet. 2011. PMID: 21946351 Free PMC article.
  • Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222.
    Enciso-Mora V, Hosking FJ, Di Stefano AL, Zelenika D, Shete S, Broderick P, Idbaih A, Delattre JY, Hoang-Xuan K, Marie Y, Labussière M, Alentorn A, Ciccarino P, Rossetto M, Armstrong G, Liu Y, Gousias K, Schramm J, Lau C, Hepworth SJ, Schoemaker M, Strauch K, Müller-Nurasyid M, Schreiber S, Franke A, Moebus S, Eisele L, Swerdlow A, Simon M, Bondy M, Lathrop M, Sanson M, Houlston RS. Enciso-Mora V, et al. Br J Cancer. 2013 May 28;108(10):2178-85. doi: 10.1038/bjc.2013.155. Epub 2013 Apr 9. Br J Cancer. 2013. PMID: 23571737 Free PMC article.
  • Rare germline variant (rs78378222) in the TP53 3' UTR: Evidence for a new mechanism of cancer predisposition in Li-Fraumeni syndrome.
    Macedo GS, Araujo Vieira I, Brandalize AP, Giacomazzi J, Inez Palmero E, Volc S, Rodrigues Paixão-Côrtes V, Caleffi M, Silva Alves M, Achatz MI, Hainaut P, Ashton-Prolla P. Macedo GS, et al. Cancer Genet. 2016 Mar;209(3):97-106. doi: 10.1016/j.cancergen.2015.12.012. Epub 2016 Jan 7. Cancer Genet. 2016. PMID: 26823150
  • A novel TP53 variant (rs78378222 A > C) in the polyadenylation signal is associated with increased cancer susceptibility: evidence from a meta-analysis.
    Wang Y, Wu XS, He J, Ma T, Lei W, Shen ZY. Wang Y, et al. Oncotarget. 2016 May 31;7(22):32854-65. doi: 10.18632/oncotarget.9056. Oncotarget. 2016. PMID: 27147571 Free PMC article. Review.
  • Tumor protein 53 mutations and inherited cancer: beyond Li-Fraumeni syndrome.
    Palmero EI, Achatz MI, Ashton-Prolla P, Olivier M, Hainaut P. Palmero EI, et al. Curr Opin Oncol. 2010 Jan;22(1):64-9. doi: 10.1097/CCO.0b013e328333bf00. Curr Opin Oncol. 2010. PMID: 19952748 Review.
See all similar articles

Cited by 53 articles

See all "Cited by" articles

Publication types

MeSH terms