Journal
BLOOD
Volume 121, Issue 22, Pages 4529-4540Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-12-471722
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Funding
- National Cancer Institute/National Institutes of Health [R01CA138688, 1RC1CA146299, P50CA136411, P50CA142509]
- Shannon Timmins Leukemia Fellowship Award at The University of Texas MD Anderson Cancer Center
- University of Texas MD Anderson Cancer Center Institutional Research and Development Fund
- Institutional Research Grant Award
- MD Anderson Cancer Center Lymphoma Specialized Programs of Research Excellence Research Development Program Award
- MD Anderson Cancer Center Myeloma Specialized Programs of Research Excellence Research Development Program Award
- Gundersen Lutheran Medical Foundation Award
- MD Anderson Cancer Center Collaborative Funds with Roche Molecular System
- HTG Molecular Diagnostics
- Daiichi Sankyo Pharmaceutical
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We identified multiple single nucleotide variants (SNVs) in the TP53 3' untranslated region (3'UTR) in tumor specimens from 244 patients with diffuse large B-cell lymphoma (DLBCL). Patients carrying a wild-type TP53 coding sequence (CDS) and 1 or more 3'UTR SNVs had a better 5-year survival rate than patients carrying a wild-type CDS and the reference 3'UTR, yet there is no statistically significance difference in overall survival (OS). In contrast, 3'UTR variation predicted poorer OS for patients with a mutant TP53 CDS. We then sequenced TP53 3'UTR in 247 additional DLBCL patients as a validation set. Altogether, we identified 187 novel SNVs; 36 occurred at least twice. Most of the newly identified 3'UTR SNVs were located at sites that are complementary to seed sequences of microRNAs (miRNAs) that are predicted or experimentally known to target TP53. Three SNVs disrupt the seed match between miR-125b and the TP53 3'UTR, thereby impeding suppression of p53 by this miRNA. In addition, a germline SNV (rs78378222) located in the TP53 polyadenylation signal resulted in downregulation of both p53 messenger RNA and protein levels and reduction of cellular apoptosis. This study is the first to demonstrate the prognostic value of the TP53 3'UTR in cancer.
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