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Quantitative evaluation of p16INK4a promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma
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 Genetics and Pathology. (Rosenquist Brandell)
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 Pathology.
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2011 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 4, 438-443 p.Article in journal (Refereed) Published
Abstract [en]

The p16INK4a tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16INK4a methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16INK4a methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16INK4a methylation in DLBCL, promoter methylation of this gene was assessed quantitatively by pyrosequencing. Forty-two of 113 (37%) DLBCL patients with methylation level above 5% were categorized as methylated and subsequently divided into low, intermediate and high methylation categories. Overall, no association was shown between the extent of p16INK4a methylation and patients’ clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16INK4a methylation on lymphoma-specific survival. Although >25% of p16INK4a methylation correlated with a better progression-free survival (P=0.048), the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16INK4a promoter methylation as a negative prognostic factor in DLBCL.

Place, publisher, year, edition, pages
2011. Vol. 35, no 4, 438-443 p.
Keyword [en]
Diffuse large B-cell lymphoma, p16INK4a, Methylation, Pyrosequencing, Lymphoma-specific survival, Progression-free survival
National Category
Hematology
Research subject
Molecular Genetics; Molecular Biology; Genetics; Oncology
Identifiers
URN: urn:nbn:se:uu:diva-114516DOI: 10.1016/j.leukres.2010.10.001ISI: 000288164600004PubMedID: 21035853OAI: oai:DiVA.org:uu-114516DiVA: diva2:295559
Available from: 2010-02-17 Created: 2010-02-17 Last updated: 2017-12-12Bibliographically 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
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Available from: 2010-03-09 Created: 2010-02-06 Last updated: 2010-03-09Bibliographically approved

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Zainuddin, NorafizaBerglund, MattiasAmini, Rose-MarieSundström, ChristerEnblad, GunillaRosenquist, Richard

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Zainuddin, NorafizaBerglund, MattiasAmini, Rose-MarieSundström, ChristerEnblad, GunillaRosenquist, Richard
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Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis
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