title: Single nucleotide variation in the TP53 3' untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP: a report from the International DLBCL Rituximab-CHOP Consortium Program.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Brown Cancer Center, Louisville, KY 40202, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Michael W
authors.initials: MW
authors.lastname: Gordon
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.forename: Alexander
authors.initials: A
authors.lastname: Tzankov
authors.forename: Dehui
authors.initials: D
authors.lastname: Zou
authors.forename: Lugui
authors.initials: L
authors.lastname: Qiu
authors.forename: Santiago
authors.initials: S
authors.lastname: Montes-Moreno
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkaer
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Richards
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.forename: William W L
authors.initials: WW
authors.lastname: Choi
authors.forename: J Han
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.forename: Weiyun
authors.initials: W
authors.lastname: Ai
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Andrés J M
authors.initials: AJ
authors.lastname: Ferreri
authors.forename: Jane N
authors.initials: JN
authors.lastname: Winter
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Go
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.forename: Michael B
authors.initials: MB
authors.lastname: Møller
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Ramos
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D035683:MicroRNAs / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D012189:Retrospective Studies; D000069283:Rituximab; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone