Li, Yong5; Gordon, Michael W5; Xu-Monette, Zijun Y5; Visco, Carlo5; Tzankov, Alexander5; Zou, Dehui5; Qiu, Lugui5; Montes-Moreno, Santiago5; Dybkær, Karen6; Orazi, Attilio5; Zu, Youli5; Bhagat, Govind5; Richards, Kristy L5; Hsi, Eric D5; Choi, William W L5; van Krieken, J Han5; Huang, Qin5; Ai, Weiyun5; Ponzoni, Maurilio5; Ferreri, Andrés J M5; Winter, Jane N5; Go, Ronald S5; Piris, Miguel A5; Møller, Michael B5; Wu, Lin5; Wang, Michael5; Ramos, Kenneth S5; Medeiros, L Jeffrey5; Young, Ken H5
1 The Faculty of Medicine, Aalborg University, VBN2 Aalborg University Hospital, The Faculty of Medicine, Aalborg University, VBN3 Klinik Medicin, The Faculty of Medicine, Aalborg University, VBN4 Blodsygdomme (Hæmatologi), The Faculty of Medicine, Aalborg University, VBN5 unknown6 Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, VBN
a report from the International DLBCL Rituximab-CHOP Consortium Program
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.