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Zainuddin, Norafiza
Publications (5 of 5) Show all publications
Zainuddin, N., Kanduri, M., Berglund, M., Lindell, M., Amini, R.-M., Roos, G., . . . Rosenquist, R. (2011). Quantitative evaluation of p16INK4a promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 35(4), 438-443
Open this publication in new window or tab >>Quantitative evaluation of p16INK4a promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma
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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, p. 438-443Article 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.

Keywords
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:nbn:se:uu:diva-114516 (URN)10.1016/j.leukres.2010.10.001 (DOI)000288164600004 ()21035853 (PubMedID)
Available from: 2010-02-17 Created: 2010-02-17 Last updated: 2017-12-12Bibliographically approved
Zainuddin, N., Murray, F., Kanduri, M., Gunnarsson, R., Smedby, K. E., Enblad, G., . . . Rosenquist, R. (2011). TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 35(2), 272-274
Open this publication in new window or tab >>TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia
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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 2, p. 272-274Article in journal (Refereed) Published
Abstract [en]

TP53 mutations in the absence of 17p-deletion correlate with rapid disease progression and poor survival in chronic lymphocytic leukemia (CLL). Herein, we determined the TP53 mutation frequency in 268 newly diagnosed CLL patients from a population-based material. Overall, we detected TP53 mutations in 3.7% of patients (n= 10), where 7/10 cases showed a concomitant 17p-deletion, confirming the high prevalence of TP53 mutation in 17p-deleted patients. Only 3 (1.1%) of the newly diagnosed patients in our cohort thereby carried TP53 mutations without 17p-deletion, a frequency that is much lower than previous reports on referral cohorts (3-6%). Our findings imply that TP53 mutations are rare at CLL onset and instead may arise during disease progression.

Keywords
Chronic lymphocytic leukemia, TP53 mutation, 17p-deletion, overall survival, time to treatment
National Category
Medical and Health Sciences
Research subject
Medical Genetics; Molecular Genetics; Molecular Biology
Identifiers
urn:nbn:se:uu:diva-115555 (URN)10.1016/j.leukres.2010.08.023 (DOI)000286460200024 ()20870288 (PubMedID)
Available from: 2010-02-17 Created: 2010-02-17 Last updated: 2017-12-12Bibliographically approved
Kaderi, M. A., Mansouri, M., Zainuddin, N., Cahill, N., Gunnarsson, R., Jansson, M., . . . Rosenquist, R. (2010). Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 34(3), 335-339
Open this publication in new window or tab >>Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia
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2010 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 34, no 3, p. 335-339Article in journal (Refereed) Published
Abstract [en]

The 309T>G polymorphism in the promoter region of the MDM2gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.

Keywords
MDM2 SNP309, Chronic lymphocytic leukemia, Binet stage, IGHV mutational status, Genomic aberrations, Prognostic markers
National Category
Medical and Health Sciences
Research subject
Clinical Genetics; Medicine; Oncology; Medical Genetics; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-111075 (URN)10.1016/j.leukres.2009.06.006 (DOI)000274529600013 ()19573916 (PubMedID)
Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2017-12-12Bibliographically approved
Zainuddin, N. (2010). Molecular Genetic Analysis in B-cell Lymphomas: A Focus on the p53 Pathway and p16INK4a. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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. p. 78
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 525
Keywords
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: 2018-01-12Bibliographically approved
Zainuddin, N., Berglund, M., Wanders, A., Ren, Z.-P., Amini, R.-M., Lindell, M., . . . Enblad, G. (2009). TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 33(1), 60-66
Open this publication in new window or tab >>TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype
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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, p. 60-66Article 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.

National Category
Medical and Health Sciences
Research subject
Clinical Genetics; Oncology; Medical Genetics; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-87756 (URN)10.1016/j.leukres.2008.06.022 (DOI)000261680400009 ()18706692 (PubMedID)
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: 2017-12-14Bibliographically approved
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