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J Natl Cancer Inst. 2014 Apr;106(4):dju047. doi: 10.1093/jnci/dju047. Epub 2014 Mar 14.

Rare variants in TP53 and susceptibility to neuroblastoma.

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Affiliations of authors: Division of Oncology (SJD, MDi, DAO, KC, KRB, MRR, JMM), Center for Childhood Cancer Research (SJD, MDi, DAO, KC, KRB, MRR, JMM), Center for Applied Genomics (HH), and Division of Genetics (HH, MDe) Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics (SJD, DAO, KRB, HH, MDe, JMM), Abramson Cancer Center (SJD, JMM), Genomics and Computational Biology, Biomedical Graduate Studies (SJD, DAO, JMM), and Department of Biostatistics and Epidemiology (MDe), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (SJD, HH, MDe, JMM); Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy (MC, AI); Ceinge-Biotecnologie Avanzate, Naples, Italy (MC, AI); University of Rome "La Sapienza," Department of Molecular Medicine, Rome, Italy (MDe).


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.

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