Publications by authors named "Norafiza Zainuddin"

11 Publications

  • Page 1 of 1

p16 Tumor Suppressor Gene Methylation in Diffuse Large B Cell Lymphoma: A Study of 88 Cases at Two Hospitals in the East Coast of Malaysia

Asian Pac J Cancer Prev 2017 10 26;18(10):2781-2785. Epub 2017 Oct 26.

Department of Biomedical Science, Kulliyyah of Allied Health Sciences, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malysia. Email:

Introduction: p16 gene plays an important role in the normal cell cycle regulation. Methylation of p16 has been reported to be one of the epigenetic events contributing to the pathogenesis of diffuse large B-cell lymphoma (DLBCL) which occurring at varying frequency. DLBCL is an aggressive and high-grade malignancy which accounts for approximately 30% of all non-Hodgkin lymphoma cases. However, little is known regarding the epigenetic alterations of p16 gene in DLBCL cases in Malaysia. Therefore, the objective of this study was to examine the status of p16 methylation in DLBCL. Methods: A total of 88 formalin-fixed paraffin-embedded DLBCL tissues retrieved from two hospitals located in the east coast of Malaysia, namely Hospital Tengku Ampuan Afzan (HTAA) Pahang and Hospital Universiti Sains Malaysia (HUSM) Kelantan, were chosen for this study. DNA specimens were isolated and subsequently subjected to bisulfite treatment prior to methylation specific-PCR. Two pairs of primers were used to amplify methylated and unmethylated regions of p16 gene. The PCR products were then separated using agarose gel electrophoresis and visualised under UV illumination. SPSS version 12.0 was utilised to perform all statistical analysis. Result: p16 methylation was detected in 65 of 88 (74%) samples. There was a significant association between p16 methylation status and patients aged >50 years old (p=0.04). Conclusion: Our study demonstrated that methylation of p16 tumor suppressor gene in our DLBCL cases is common and significantly increased among patients aged 50 years and above. Aging is known to be an important risk factor in the development of cancers and we speculate that this might be due to the increased transformation of malignant cells in aging cell population. However, this has yet to be confirmed with further research and correlate the findings with clinicopathological parameters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22034/APJCP.2017.18.10.2781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747404PMC
October 2017

The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma.

Eur J Haematol 2014 Dec 21;93(6):500-8. Epub 2014 Jun 21.

Department of Radiology, Oncology and Radiation Sciences, Section of Oncology, Uppsala University, Uppsala, Sweden.

Introduction: The murine double minute 2 (MDM2) gene encodes a regulatory protein of the p53 pathway. A single nucleotide polymorphism (T to G change) at position 309 (SNP309) in the promotor region of MDM2 affects the transcription activity of MDM2 and has been found to be a negative prognostic marker in several cancers.

Patients And Methods: In this study, the MDM2 SNP309 polymorphism was analysed in 201 patients with diffuse large B-cell lymphoma and analysed in relation to clinical characteristics and prognosis.

Results: Patients homozygous for SNP309T had a significantly longer overall survival, lymphoma-specific survival and disease-free survival (P = 0.002; 0.004 and 0.006 respectively) compared to patients carrying a G allele. The longer overall survival was seen in the subgroup of patients not treated with Rituximab, however, not for Rituximab-treated patients (P = 0.01 and 0.2 respectively). The group homozygous for the T allele also had lower age at diagnosis, a tendency towards lower aaIPI and a significantly lower proportion of patients with p53 aberrations compared to the group including at least one G allele. However, the survival differences persisted even after removal of cases with known p53 aberrations from the analysis.

Conclusion: Polymorphism in MDM2 SNP309 could be correlated to some clinical characteristics and for patients not treated with immunotherapy, a G allele was correlated to poor survival, whereas no survival differences were found for patients treated with Rituximab. Herewith, we provide additional information about Diffuse large B-cell Lymphoma (DLBCL) biology and highlight the importance of evaluation of molecular markers in relation to treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.12388DOI Listing
December 2014

Quantitative evaluation of p16(INK4a) promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma.

Leuk Res 2011 Apr 29;35(4):438-43. Epub 2010 Oct 29.

Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.

The p16(INK4a) tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16(INK4a) methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16(INK4a) methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16(INK4a) 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 p16(INK4a) methylation and patients' clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16(INK4a) methylation on lymphoma-specific survival. Although >25% of p16(INK4a) methylation correlated with a better progression-free survival (P=0.048) in patients <65 years old, the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16(INK4a) promoter methylation as a negative prognostic factor in DLBCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2010.10.001DOI Listing
April 2011

TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia.

Leuk Res 2011 Feb 25;35(2):272-4. Epub 2010 Sep 25.

Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala SE-751 85, Sweden.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2010.08.023DOI Listing
February 2011

Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia.

Leuk Res 2010 Mar 1;34(3):335-9. Epub 2009 Jul 1.

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.

The 309T>G polymorphism in the promoter region of the MDM2 gene, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2009.06.006DOI Listing
March 2010

TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype.

Leuk Res 2009 Jan 15;33(1):60-6. Epub 2008 Aug 15.

Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2008.06.022DOI Listing
January 2009

Association of loss of heterozygosity and PTEN gene abnormalities with paraclinical, clinical modalities and survival time of glioma patients in Malaysia.

Asian J Surg 2006 Oct;29(4):274-82

Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Background: The pattern of allelic loss of heterozygosity (LOH) and PTEN mutations appear to be associated with the progression of gliomas leading to a decrement in the survival rate of patients. This present study was carried out to determine the LOH and PTEN mutational status in glioma patients and its association with patients' survival.

Methods: Thirty-seven Malaysian glioma patients of the Malay race were subject to PTEN mutational analysis and the presence of LOH using the cold single-strand conformation polymorphism method, and their clinical and paraclinical response were correlated.

Results: Among analysed glioma patients, seven (21.6%) cases with PTEN mutations were detected and 12 (32.4%) of 37 patients showed presence of LOH. Univariate analysis showed that tumour grade, vascularization, PTEN mutation, LOH and combination of both PTEN mutation and LOH were significantly associated with glioma patients' survival. Multivariate analysis revealed that no factors contributed to survival time.

Conclusion: The results show that PTEN mutation and LOH are quite frequent in Malaysian glioma patients. However, they have no impact on the survival outcome of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1015-9584(09)60102-0DOI Listing
October 2006

Molecular genetic analysis of phosphatase and tensin homolog and p16 tumor suppressor genes in patients with malignant glioma.

Neurosurg Focus 2003 Apr 15;14(4):e6. Epub 2003 Apr 15.

Neuroscience Unit, Human Genome Centre, and Department of Pathology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan.

Object: Several genes have been shown to carry mutations in human malignant gliomas, including the phosphatase and tensin homolog (PTEN) deleted on chromosome 10 and p16 tumor suppressor genes. Alterations of this gene located on chromosome 10 q23 and 9p21, respectively, may contribute to gliomagenesis. In this study, the authors analyzed 20 cases of malignant gliomas obtained in patients living on the east coast of Malaysia to investigate the possibilities of involvement of the PTEN and p16 genes.

Methods: Samples of DNA were amplified by polymerase chain reaction (PCR), analyzed by single-stranded conformation polymorphism (SSCP), and subsequently by sequencing. Two cases of glioblastoma multiforme, three cases of anaplastic astrocytoma, one case of anaplastic pleomorphic xanthoastrocytoma, and one case of anaplastic ependymoma showed SSCP band shifts in PTEN mutational analyses. The DNA sequencing analyses of these samples revealed missense and nonsense mutations, with cluster of mutations in the region 5' to the core phosphatase motif of exon 5 and the 5'-end of exon 6. No abnormal migration shifts were detected in the glioma samples analyzed for point mutations of the p16 gene. Homozygous deletions of p16 were also not detected in all samples.

Conclusions: These findings indicate that mutations of the PTEN genes were likely to contribute to the tumorigenesis and morphological transformations of gliomas. In addition, the alterations of the p16 gene might not play a major role in tumorigenesis of malignant gliomas in Malaysian patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/foc.2003.14.4.6DOI Listing
April 2003

Loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in malays with malignant glioma.

Neurol Res 2004 Jan;26(1):88-92

Human Genome Centre, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia.

Recent advances in neuro-oncology have revealed different pathways of molecular oncogenesis in malignant gliomas including loss of heterozygosity on chromosomal regions harboring tumor suppressor genes. In the present study, we performed polymerase chain reaction-loss of heterozygosity (PCR-LOH) analysis using microsatellite markers to identify loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in the Malays with malignant gliomas. Of 12 cases with allelic losses, seven (58.3%) cases showed LOH on chromosome 10q, three (25.0%) cases showed LOH on chromosome 9p, four (33.3%) cases showed LOH on chromosome 17p and two (16.7%) cases showed LOH on chromosome 13q. The cases include five (41.7%) cases of glioblastoma multiforme, three (25.0%) cases of anaplastic astrocytoma, three (25.0%) cases of anaplastic oligodendroglioma and one (8.3%) case of anaplastic ependymoma. Four cases showed loss of heterozygosity on more than one locus. Our findings showed that loss of heterozygosity on specific chromosomal regions contributes to the molecular pathway of glioma progression in Malay population. In addition, these data provide useful evidence of molecular genetic alterations of malignant glioma in South East Asian patients, particularly in the East Coast of Malaysia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1179/016164104773026598DOI Listing
January 2004

What We Know about the Molecular Genetics of Central Nervous System (CNS) Tumours in Malaysia.

Malays J Med Sci 2004 Jan;11(1):37-43

Human Genome Center, Department of Neurosciences.

The new millennium has been regarded as a genomic era. A lot of researchers and pathologists are beginning to understand the scientific basis of molecular genetics and relates with the progression of the diseases. Central nervous system (CNS) tumours are among the most rapidly fatal of all cancers. It has been proposed that the progression of malignant tumours may result from multi-step of genetic alterations, including activation of oncogenes, inactivation of tumour suppressor genes and also the presence of certain molecular marker such as telomerase activity. In this paper, we review some recent data from the literature, including our own studies, on the molecular genetics analysis in CNS tumours. Our studies have shown that two types of tumour suppressor genes, p53 and PTEN were involved in the development of these tumours but not in p16 gene among the patients from Hospital Universiti Sains Malaysia (HUSM). Telomerase activity also has been detected in various types of CNS tumours. Thus, it is important to assemble all data which related to this study and may provide as a vital information in a new approach to neuro-oncology studies in Malaysia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438149PMC
January 2004

Molecular genetic analysis of anaplastic pleomorphic xanthoastrocytoma.

Asian J Surg 2003 Apr;26(2):120-5

Department of Neuroscience, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

A case of pleomorphic xanthoastrocytoma in a 10-year-old Malay boy is reported. The patient presented with headache and epilepsy. On computed tomography, a ring-enhancing low-density lesion was observed in the left fronto-temporal area. During surgery, a cystic tumour containing serous fluid was found and almost totally removed. Histologically, the tumour exhibited marked pleomorphism of oval and spindle-shaped cells intermixed with uni- and multinucleated giant cells, and xanthomatous cells with foamy cytoplasm. The tumour displayed pericellular reticulin and periodic acid-Schiff positive granules. Focally, six mitotic characters per 10 high-power fields were seen, and necrosis was confined only to the inner lining of the cyst. Mutational analysis showed that a frameshift mutation (a 4-bp deletion) in the p53 gene had occurred in codons 273 and 274 of exon 8. No mutation was detected in the p16 gene. No allelic loss and/or loss of heterozygosity were observed on chromosome 10 using microsatellite marker D105532. The patient was treated with postoperative radiotherapy because of histological anaplasia and the presence of residual tumour. The patient showed marked neurological recovery after a follow-up period of 2 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1015-9584(09)60233-5DOI Listing
April 2003