AI Article Synopsis
- TP53 is the most commonly mutated gene in human cancers, but somatic mutations are rare in childhood cancers like neuroblastoma.
- A study of 10,290 individuals found two rare germline variants, rs78378222 and rs35850753, significantly associated with neuroblastoma, suggesting they increase cancer risk.
- These variants affect TP53 transcript processing, indicating a potential mechanism by which they contribute to the development of neuroblastoma, and future research may identify more impactful mutations.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982892 | PMC |
| http://dx.doi.org/10.1093/jnci/dju047 | DOI Listing |
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