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TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. (Lymphoma (Gunilla Enblad))
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. (Lymphoma)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology. (Wanders)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2009 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 33, no 1, 60-66 p.Article in journal (Refereed) Published
Abstract [en]

Presence of TP53 mutations has been associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), although this has remained controversial. The TP53 codon 72 polymorphism has shown negative impact on cancer survival, but this has not been analyzed in DLBCL. Furthermore, the MDM2 SNP309 has been associated with earlier age of onset in DLBCL. Here, we investigated the clinical impact of TP53 mutations, MDM2 SNP309 and TP53 codon 72 polymorphisms on survival in DLBCL of germinal center (GC) and non-GC subtypes. Thirteen of the 102 (12.7%) patients displayed TP53 mutations. Overall, TP53 mutations had a significant effect on lymphoma-specific survival (LSS, P=0.009) and progression-free survival (PFS, P=0.028). In particular, inferior survival was observed in TP53-mutated DLBCLs of GC subtype (LSS, P=0.002 and PFS, P=0.006). Neither MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. Altogether, our data suggests that TP53 mutations are associated with poor outcome in GC-DLBCL patients.

Place, publisher, year, edition, pages
2009. Vol. 33, no 1, 60-66 p.
National Category
Medical and Health Sciences
Research subject
Clinical Genetics; Oncology; Medical Genetics; Molecular Genetics
Identifiers
URN: urn:nbn:se:uu:diva-87756DOI: 10.1016/j.leukres.2008.06.022ISI: 000261680400009PubMedID: 18706692OAI: oai:DiVA.org:uu-87756DiVA: diva2:133554
Projects
TP53 mutation, MDM2 SNP309, TP53 codon 72 polymorphism, Diffuse large B-cell lymphoma, Germinal center subtype, Survival
Available from: 2010-02-15 Created: 2009-01-12 Last updated: 2010-08-10Bibliographically approved
In thesis
1. Molecular Genetic Analysis in B-cell Lymphomas: A Focus on the p53 Pathway and p16INK4a
Open this publication in new window or tab >>Molecular Genetic Analysis in B-cell Lymphomas: A Focus on the p53 Pathway and p16INK4a
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The presence of TP53 mutations has been associated with inferior outcome in diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In DLBCL, the impact of the TP53 codon 72 polymorphism and MDM2 SNP309 has not been clearly elucidated, whereas MDM2 SNP309 was suggested as a poor-prognostic marker in CLL. In addition, p16INK4a promoter hypermethylation has been implicated as a negative prognostic factor in DLBCL. The aim of this thesis was to further evaluate these molecular markers in well-characterised materials of DLBCL and CLL.

In paper I, we investigated the prognostic role of TP53 mutation, codon 72 polymorphism and MDM2 SNP309 in DLBCL (n=102). The presence of TP53 mutations (12.7%) correlated with a poor lymphoma-specific and progression-free survival, and a particularly pronounced effect was observed in the germinal center subtype. Neither the MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. In paper II, we applied pyrosequencing to measure the level of p16INK4a methylation in DLBCL (n=113). Thirty-seven percent of cases displayed p16INK4a methylation; however, no clear association could be observed between degree of methylation and clinical characteristics or lymphoma-specific survival.

In papers III–IV, we investigated the prognostic role of MDM2 SNP309 (n=418) and TP53 mutation (n=268) in CLL. No correlation was observed between any particular MDM2 SNP309 genotype and time to treatment and overall survival. Furthermore, no association was found between the different MDM2 SNP309 genotypes and established CLL prognostic markers. TP53 mutations were detected in 3.7% of CLL patients; where the majority showed a concomitant 17p-deletion and only three carried TP53 mutations without 17p-deletion. We confirmed a significantly shorter overall survival and time to treatment in patients with both TP53 mutation and 17p-deletion.

Altogether, our studies could confirm the negative prognostic impact of TP53 mutations in DLBCL, whereas MDM2 SNP309 and TP53 codon 72 polymorphisms appear to lack clinical relevance. We also question the role of p16INKa methylation as a poor-prognostic factor in DLBCL. Finally, the presence of TP53 mutation in CLL appears to be rare at disease onset and instead arise during disease progression.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 525
Keyword
Diffuse large B-cell lymphoma, chronic lymphocytic leukemia, TP53 mutation, MDM2 SNP309, codon 72 polymorphism, p16INK4a methylation
National Category
Medical Genetics Cell and Molecular Biology Hematology Cell and Molecular Biology
Research subject
Clinical Genetics; Medical Genetics; Molecular Genetics; Oncology; Pathology
Identifiers
urn:nbn:se:uu:diva-113970 (URN)978-91-554-7729-5 (ISBN)
Public defence
2010-03-31, Auditorium Minus, Akademigatan 3, 75310, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2010-03-09 Created: 2010-02-06 Last updated: 2010-03-09Bibliographically approved

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Zainuddin, NorafizaAmini, Rose-MarieKanduri, MeenaRosenquist, Richard

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Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis
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