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.

Yong Li, Michael W. Gordon, Zijun Y. Xu-Monette, Carlo Visco, Alexander Tzankov, Dehui Zou, Lugui Qiu, Santiago Montes-Moreno, Karen Dybkaer, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W L Choi, J. Han van Krieken, Qin Huang, Weiyun Ai, Maurilio Ponzoni, Andrés J M Ferreri & 9 others Jane N. Winter, Ronald S. Go, Miguel A. Piris, Michael B. Møller, Lin Wu, Michael Wang, Kenneth S. Ramos, L. Jeffrey Medeiros, Ken H. Young

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4529-4540
Number of pages12
JournalBlood
Volume121
Issue number22
DOIs
StatePublished - May 30 2013
Externally publishedYes

Fingerprint

Lymphoma, Large B-Cell, Diffuse
3' Untranslated Regions
Nucleotides
Cells
MicroRNAs
Seed
Seeds
Polyadenylation
Survival
Rituximab
Tumors
Neoplasms
Down-Regulation
Survival Rate
Apoptosis
Messenger RNA

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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. / Li, Yong; Gordon, Michael W.; Xu-Monette, Zijun Y.; Visco, Carlo; Tzankov, Alexander; Zou, Dehui; Qiu, Lugui; Montes-Moreno, Santiago; Dybkaer, Karen; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L.; Hsi, Eric D.; Choi, William W L; van Krieken, J. Han; Huang, Qin; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J M; Winter, Jane N.; Go, Ronald S.; Piris, Miguel A.; Møller, Michael B.; Wu, Lin; Wang, Michael; Ramos, Kenneth S.; Medeiros, L. Jeffrey; Young, Ken H.

In: Blood, Vol. 121, No. 22, 30.05.2013, p. 4529-4540.

Research output: Contribution to journalArticle

Li, Y, Gordon, MW, Xu-Monette, ZY, Visco, C, Tzankov, A, Zou, D, Qiu, L, Montes-Moreno, S, Dybkaer, K, Orazi, A, Zu, Y, Bhagat, G, Richards, KL, Hsi, ED, Choi, WWL, van Krieken, JH, Huang, Q, Ai, W, Ponzoni, M, Ferreri, AJM, Winter, JN, Go, RS, Piris, MA, Møller, MB, Wu, L, Wang, M, Ramos, KS, Medeiros, LJ & Young, KH 2013, '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.', Blood, vol. 121, no. 22, pp. 4529-4540. https://doi.org/10.1182/blood-2012-12-471722
Li, Yong ; Gordon, Michael W. ; Xu-Monette, Zijun Y. ; Visco, Carlo ; Tzankov, Alexander ; Zou, Dehui ; Qiu, Lugui ; Montes-Moreno, Santiago ; Dybkaer, Karen ; Orazi, Attilio ; Zu, Youli ; Bhagat, Govind ; Richards, Kristy L. ; Hsi, Eric D. ; Choi, William W L ; van Krieken, J. Han ; Huang, Qin ; Ai, Weiyun ; Ponzoni, Maurilio ; Ferreri, Andrés J M ; Winter, Jane N. ; Go, Ronald S. ; Piris, Miguel A. ; Møller, Michael B. ; Wu, Lin ; Wang, Michael ; Ramos, Kenneth S. ; Medeiros, L. Jeffrey ; Young, Ken H. / 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. In: Blood. 2013 ; Vol. 121, No. 22. pp. 4529-4540.
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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.",
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T1 - Single nucleotide variation in the TP53 3' untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP

T2 - a report from the International DLBCL Rituximab-CHOP Consortium Program.

AU - Li, Yong

AU - Gordon, Michael W.

AU - Xu-Monette, Zijun Y.

AU - Visco, Carlo

AU - Tzankov, Alexander

AU - Zou, Dehui

AU - Qiu, Lugui

AU - Montes-Moreno, Santiago

AU - Dybkaer, Karen

AU - Orazi, Attilio

AU - Zu, Youli

AU - Bhagat, Govind

AU - Richards, Kristy L.

AU - Hsi, Eric D.

AU - Choi, William W L

AU - van Krieken, J. Han

AU - Huang, Qin

AU - Ai, Weiyun

AU - Ponzoni, Maurilio

AU - Ferreri, Andrés J M

AU - Winter, Jane N.

AU - Go, Ronald S.

AU - Piris, Miguel A.

AU - Møller, Michael B.

AU - Wu, Lin

AU - Wang, Michael

AU - Ramos, Kenneth S.

AU - Medeiros, L. Jeffrey

AU - Young, Ken H.

PY - 2013/5/30

Y1 - 2013/5/30

N2 - 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.

AB - 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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DO - 10.1182/blood-2012-12-471722

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