Publications by authors named "Sarina Sulong"

23 Publications

  • Page 1 of 1

The Unique Biology behind the Early Onset of Breast Cancer.

Genes (Basel) 2021 Mar 5;12(3). Epub 2021 Mar 5.

Department of Pathology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan 16150, Malaysia.

Breast cancer commonly affects women of older age; however, in developing countries, up to 20% of breast cancer cases present in young women (younger than 40 years as defined by oncology literature). Breast cancer in young women is often defined to be aggressive in nature, usually of high histological grade at the time of diagnosis and negative for endocrine receptors with poor overall survival rate. Several researchers have attributed this aggressive nature to a hidden unique biology. However, findings in this aspect remain controversial. Thus, in this article, we aimed to review published work addressing somatic mutations, chromosome copy number variants, single nucleotide polymorphisms, differential gene expression, microRNAs and gene methylation profile of early-onset breast cancer, as well as its altered pathways resulting from those aberrations. Distinct biology behind early-onset of breast cancer was clear among estrogen receptor-positive and sporadic cases. However, further research is needed to determine and validate specific novel markers, which may help in customizing therapy for this group of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12030372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000244PMC
March 2021

Identification of Copy Number Variation Among Nonsyndromic Cleft Lip and or Without Cleft Palate With Hypodontia: A Genome-Wide Association Study.

Front Physiol 2021 26;12:637306. Epub 2021 Feb 26.

School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia.

Nonsyndromic cleft lip and or without cleft palate (NSCL/P) with the hypodontia is a common developmental abnormality in humans and animals. This study identified the genetic aberration involved in both NSCL/P and hypodontia pathogenesis. A cross-sectional study using genome-wide study copy number variation-targeted CytoScan 750K array carried out on salivary samples from 61 NSCL/P and 20 noncleft with and without hypodontia Malay subjects aged 7-13 years old. Copy number variations (CNVs) of and fragile histidine triad () were identified in NSCL/P and noncleft children using quantitative polymerase chain reaction (qPCR) as a validation analysis. Copy number calculated (CNC) for each gene determined with Applied Biosystems CopyCaller Software v2.0. The six significant CNVs included gains (12q14.3, 15q26.3, 1p36.32, and 1p36.33) and losses (3p14.2 and 4q13.2) in NSCL/P with hypodontia patients compared with the NSCL/P only. The genes located in these regions encoded , , , , , and . There were a significant gain and loss of both and copy number in NSCL/P with hypodontia compared with the noncleft group ( < 0.05). The results supported that CNVs significantly furnish to the development of NSCL/P with hypodontia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2021.637306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959817PMC
February 2021

Impact of Fas/Fasl Gene Polymorphisms on Susceptibility Risk and Imatinib Mesylate Treatment Response in Chronic Myeloid Leukaemia Patients.

Asian Pac J Cancer Prev 2021 Feb 1;22(2):565-571. Epub 2021 Feb 1.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Background: The FAS mediated apoptosis pathway involving the FAS and FASL genes plays a crucial role in the regulation of apoptotic cell death and imatinib mesylate (IM) mechanism of action. Promoter polymorphisms FAS-670 A>G and FAS-844 T>C which alter the transcriptional activity of these genes may grant a risk to develop cancer and revamp the drug activities towards the cancer cell. We investigated the association of these two polymorphisms with the susceptibility risk and IM treatment response in Malaysian chronic myeloid leukaemia (CML) patients.

Methods: This is a retrospective study, which included 93 CML patients and 98 controls. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method was used to genotype the FAS and FASL polymorphisms. Data nanlysis was done using SPSS Version 22. The associations of the genotypes with susceptibility risk and IM response in CML patients were assessed by means of logistic regression analysis and deriving odds ratio with 95% CI.

Results: We observed a significant association between FASL-844T>C polymorphism and CML susceptibility risk and IM response. Variant C allele and FASL-844 CC variant genotype carriers had significantly higher risk for CML susceptibility (OR 1.756, CI 1.163-2.652, p=0.007 and OR 2.261, CI 1.013-5.047, p=0.047 respectively). Conversely, the heterozygous genotype FASL-844 TC conferred lower risk for CML susceptibility (OR 0.379, CI 0.176-0.816, p=0.013). The heterozygous and homozygous variant genotypes and variant C alleles were found to confer a lower risk for the development of IM resistance with OR 0.129 (95% CI: 0.034-0.489 p=0.003), OR 0.257 (95% CI: 0.081-0.818, p=0.021), and OR 0.486 (95% CI: 0.262-0.899, p=0.021) respectively. We also found that FAS-670 A>G polymorphism was not associated with CML susceptibility risk or IM response.

Conclusion: The genetic polymorphism FASL-844 T>C may contribute to the CML susceptibility risk and also IM treatment response in CML patients. Accodringly, it may be useful as a biomarker for predicting CML susceptibility risk and IM resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.31557/APJCP.2021.22.2.565DOI Listing
February 2021

Aberrant Methylation of Tumour Suppressor Gene ADAM12 in Chronic Lympocytic Leukemia Patients: Application of Methylation Specific-PCR Technique.

Asian Pac J Cancer Prev 2021 Jan 1;22(1):85-91. Epub 2021 Jan 1.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Objective: Chronic Lymphocytic Leukemia (CLL) is a common leukemia among Caucasians but rare in Asians population. We postulated that aberrant methylation either hypermethylation or partial methylation might be one of the silencing mechanisms that inactivates the tumour suppressor genes in CLL. This study aimed to compare the methylation status of tumour suppressor gene, ADAM12, among CLL patients and normal individuals. We also evaluated the association between methylation of ADAM12 and clinical and demographic characteristics of the participants.

Methods: A total of 25 CLL patients and 25 normal individuals were recruited in this study. The methylation status of ADAM12 was determined using Methylation-Specific PCR (MSP); whereas, DNA sequencing method was applied for validation of the MSP results.

Results: Among CLL patients, 12 (48%) were partially methylated and 13 (52%) were unmethylated. Meanwhile, 5 (20%) and 20 (80.6%) of healthy individuals were partially methylated and unmethylated, respectively. There was a statistically significant association between the status of methylation at ADAM12 and the presence of CLL (p=0.037).

Conclusion: The aberrant methylation of ADAM12 found in this study using MSP assay may provide new exposure to CLL that may improve the gaps involved in genetic epigenetic study in CLL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.31557/APJCP.2021.22.1.85DOI Listing
January 2021

Telomerase reverse transcriptase downregulation by RNA interference modulates endoplasmic reticulum stress and mitochondrial energy production.

Mol Biol Rep 2020 Oct 21;47(10):7735-7743. Epub 2020 Sep 21.

Institute of Biological Sciences, Faculty of Science, University Malaya, 50603, Kuala Lumpur, Malaysia.

Telomerase is a cancer promoting ribonucleoprotein complex and is a potential therapeutic target for cancer. In this study, the effects of telomerase downregulation on the whole cell proteome were investigated. Understanding how the effect of downregulation on the whole proteome profile will generate a greater understanding of the possible roles played by telomerase in cancer. Downregulation was achieved by RNA interference (RNAi), targeting the telomerase reverse transcriptase (TERT) subunits of telomerase. Transfection of TERT siRNA downregulates TERT gene expression and induced downregulation of telomerase activity. Investigation of the effect of silencing TERT in telomerase was further validated through proteomic analysis by performing 2-dimension electrophoresis (2DE) coupled with MALDI-TOF/TOF. 12 protein spots in HeLa cells were reported to be significantly differentially expressed with 11 of them were upregulated and 1 downregulated. Through STRING analysis, differentially expressed proteins demonstrated strong associations with endoplasmic reticulum stress marker and mitochondrial energy production marker. In conclusions, the result exhibited novel integrated proteomic response involving endoplasmic reticulum stress and mitochondrial energy production in response to the TERT downregulation in cervical cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11033-020-05848-yDOI Listing
October 2020

Ancestry-informative marker (AIM) SNP panel for the Malay population.

Int J Legal Med 2020 Jan 23;134(1):123-134. Epub 2019 Nov 23.

Department of Paediatrics, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.

Ancestry-informative markers (AIMs) can be used to infer the ancestry of an individual to minimize the inaccuracy of self-reported ethnicity in biomedical research. In this study, we describe three methods for selecting AIM SNPs for the Malay population (Malay AIM panel) using different approaches based on pairwise F, informativeness for assignment (I), and PCA-correlated SNPs (PCAIMs). These Malay AIM panels were extracted from genotype data stored in SNP arrays hosted by the Malaysian node of the Human Variome Project (MyHVP) and the Singapore Genome Variation Project (SGVP). In particular, genotype data from a total of 165 Malay individuals were analyzed, comprising data on 117 individual genotypes from the Affymetrix SNP-6 SNP array platform and data on 48 individual genotypes from the OMNI 2.5 Illumina SNP array platform. The HapMap phase 3 database (1397 individuals from 11 populations) was used as a reference for comparison with the Malay genotype data. The accuracy of each resulting Malay AIM panel was evaluated using a machine learning "ancestry-predictive model" constructed by using WEKA, a comprehensive machine learning platform written in Java. A total of 1250 SNPs were finally selected, which successfully identified Malay individuals from other world populations with an accuracy of 90%, but the accuracy decreased to 80% using 157 SNPs according to the pairwise F method, while a panel of 200 SNPs selected using I and PCAIMs could be used to identify Malay individuals with an accuracy of approximately 80%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00414-019-02184-0DOI Listing
January 2020

Microvascular endothelial function and primary open angle glaucoma.

Ther Adv Ophthalmol 2019 Jan-Dec;11:2515841419868100. Epub 2019 Aug 22.

Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kota Bharu, Kelantan Malaysia.

Purpose: To determine the role of microvascular endothelial dysfunction as risk factor for primary open angle glaucoma.

Methods: A cross-sectional study was conducted involving 114 Malay patients with POAG seen at the eye clinic of Hospital Universiti Sains Malaysia. Patients aged between 40 and 80 years who were diagnosed with other types of glaucoma, previous glaucoma filtering surgery or other surgeries except uncomplicated cataract surgery and pterygium surgery were excluded. A total of 101 patients who were followed up for dry eyes, age-related cataracts or post cataracts extraction surgery were recruited as control subjects. Those with family history of glaucoma or glaucoma suspect were excluded. Microvascular endothelial function was assessed using laser Doppler fluximetry and the process of iontophoresis. Iontophoresis with acetylcholine (ACh) and sodium nitroprusside (SNP) was used to measure microvascular endothelium-dependent and endothelium-independent vasodilatations, respectively.

Results: In general, POAG patients demonstrated lower ACh% and ACh values compared with controls. There was significant difference in microvascular endothelial function [ACh%: mean, 95% confidence interval = 503.1 (378.0, 628.3), and ACh: mean, 95% confidence interval = 36.8 (30.2, 43.5)] between primary open angle glaucoma cases ( < 0.001) and controls [ACh%: mean, 95% confidence interval = 1378.4 (1245.4, 1511.3), and ACh: mean, 95% confidence interval = 79.2 (72.1, 86.2)]; this difference remained significant even after controlling for potential confounders. Similar difference was also found in SNP% and SNP between POAG and controls ( < 0.001). Age and diastolic blood pressure were inversely correlated with microvascular endothelial function.

Conclusion: There was an impairment of microvascular endothelial function and endothelial-independent vasodilatation in POAG patients. Microvascular endothelial function is a potential risk factor for POAG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2515841419868100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710703PMC
August 2019

Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and/or palate.

Mol Genet Genomic Med 2019 05 28;7(5):e635. Epub 2019 Mar 28.

Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Background: Nonsyndromic cleft lip and/or palate is one of the most common human birth defects worldwide that affects the lip and/or palate. The incidence of clefts varies among populations through ethnic, race, or geographical differences. The focus on Malay nonsyndromic cleft lip and/or palate (NSCL/P) is because of a scarce report on genetic study in relation to this deformity in Malaysia. We are interested to discuss about the genes that are susceptible to cause orofacial cleft formation in the family.

Methods: Genome-wide linkage analysis was carried out on eight large extended families of NSCL/P with the total of 91 individuals among Malay population using microarray platform. Based on linkage analyses findings, copy number variation (CNV) of LPHN2, SATB2, PVRL3, COL21A1, and TOX3 were identified in four large extended families that showed linkage evidence using quantitative polymerase chain reaction (qPCR) as for a validation purpose. Copy number calculated (CNC) for each genes were determined with Applied Biosystems CopyCallerTM Software v2.0. Normal CNC of the target sequence expected was set at two.

Results: Genome-wide linkage analysis had discovered several genes including TOX3 and COL21A1 in four different loci 4p15.2-p16.1, 6p11.2-p12.3, 14q13-q21, and 16q12.1. There was significant decreased, p < 0.05 of SATB2, COL21A1, and TOX3 copy number in extended families compared to the normal controls.

Conclusion: Novel linkage evidence and significant low copy number of COL21A1 and TOX3 in NSCLP family was confirmed. These genes increased the risks toward NSCLP formation in that family traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503016PMC
May 2019

Aberrant DNA methylation at HOXA4 and HOXA5 genes are associated with resistance to imatinib mesylate among chronic myeloid leukemia patients.

Cancer Rep (Hoboken) 2018 08 27;1(2):e1111. Epub 2018 Jul 27.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Background: Imatinib mesylate is a molecularly targeted tyrosine kinase inhibitor drug. It is effectively used in the treatment of chronic myeloid leukemia (CML) patients. However, development of resistance to imatinib mesylate as a result of BCR-ABL dependent and BCR-ABL independent mechanisms has emerged as a daunting problem in the management of CML patients. Between these mechanisms, BCR-ABL independent mechanisms are still not robustly understood.

Aim: To investigate the correlation of HOXA4 and HOXA5 promoter DNA hypermethylation with imatinib resistance among CML patients.

Methods And Results: Samples from 175 Philadelphia positive CML patients (83 good response and 92 BCR-ABL non-mutated imatinib resistant patients) were subjected to Methylation Specific High Resolution Melt Analysis for methylation levels quantification of the HOXA4 and HOXA5 promoter regions. Receiver operating characteristic curve analysis was done to elucidate the optimal methylation cut-off point followed by multiple logistic regression analysis. Log-Rank analysis was done to measure the overall survival difference between CML groups. The optimal methylation cut-off point was found to be at 62.5% for both HOXA4 and HOXA5. Chronic myeloid leukemia patients with ≥63% HOXA4 and HOXA5 methylation level were shown to have 3.78 and 3.95 times the odds, respectively, to acquire resistance to imatinib. However, overall survival of CML patients that have ≤62% and ≥ 63% methylation levels of HOXA4 and HOXA5 genes were found to be not significant (P-value = 0.126 for HOXA4; P-value = 0.217 for HOXA5).

Conclusion: Hypermethylation of the HOXA4 and HOXA5 promoter is correlated with imatinib resistance and with further investigation, it could be a potential epigenetic biomarker in supplement to the BCR-ABL gene mutation in predicting imatinib treatment response among CML patients but could not be considered as a prognostic marker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cnr2.1111DOI Listing
August 2018

Analysis of the genetic structure of the Malay population: Ancestry-informative marker SNPs in the Malay of Peninsular Malaysia.

Forensic Sci Int Genet 2017 09 14;30:152-159. Epub 2017 Jul 14.

Department of Paediatric, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150 Kelantan, Malaysia. Electronic address:

Malay, the main ethnic group in Peninsular Malaysia, is represented by various sub-ethnic groups such as Melayu Banjar, Melayu Bugis, Melayu Champa, Melayu Java, Melayu Kedah Melayu Kelantan, Melayu Minang and Melayu Patani. Using data retrieved from the MyHVP (Malaysian Human Variome Project) database, a total of 135 individuals from these sub-ethnic groups were profiled using the Affymetrix GeneChip Mapping Xba 50-K single nucleotide polymorphism (SNP) array to identify SNPs that were ancestry-informative markers (AIMs) for Malays of Peninsular Malaysia. Prior to selecting the AIMs, the genetic structure of Malays was explored with reference to 11 other populations obtained from the Pan-Asian SNP Consortium database using principal component analysis (PCA) and ADMIXTURE. Iterative pruning principal component analysis (ipPCA) was further used to identify sub-groups of Malays. Subsequently, we constructed an AIMs panel for Malays using the informativeness for assignment (I) of genetic markers, and the K-nearest neighbor classifier (KNN) was used to teach the classification models. A model of 250 SNPs ranked by I, correctly classified Malay individuals with an accuracy of up to 90%. The identified panel of SNPs could be utilized as a panel of AIMs to ascertain the specific ancestry of Malays, which may be useful in disease association studies, biomedical research or forensic investigation purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fsigen.2017.07.005DOI Listing
September 2017

Discovery of candidate genes for nonsyndromic cleft lip palate through genome-wide linkage analysis of large extended families in the Malay population.

BMC Genet 2016 Feb 11;17:39. Epub 2016 Feb 11.

School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia.

Background: Nonsyndromic orofacial clefts are one of the most common birth defects worldwide. It occurs as a result of genetic or environmental factors. This study investigates the genetic contribution to nonsyndromic cleft lip and/or palate through the analysis of family pedigrees. Candidate genes associated with the condition were identified from large extended families from the Malay population.

Results: A significant nonparametric linkage (NPL) score was detected in family 100. Other suggestive NPL and logarithm of the odds (LOD) scores were attained from families 50, 58, 99 and 100 under autosomal recessive mode. Heterogeneity LOD (HLOD) score ≥ 1 was determined for all families, confirming genetic heterogeneity of the population and indicating that a proportion of families might be linked to each other. Several candidate genes in linkage intervals were determined; LPHN2 at 1p31, SATB2 at 2q33.1-q35, PVRL3 at 3q13.3, COL21A1 at 6p12.1, FOXP2 at 7q22.3-q33, FOXG1 and HECTD1 at 14q12 and TOX3 at 16q12.1.

Conclusions: We have identified several novel and known candidate genes for nonsyndromic cleft lip and/or palate through genome-wide linkage analysis. Further analysis of the involvement of these genes in the condition will shed light on the disease mechanism. Comprehensive genetic testing of the candidate genes is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12863-016-0345-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751652PMC
February 2016

Guidelines for nucleic acid detection and analysis in hematological disorders.

Malays J Pathol 2015 Aug;37(2):165-73

Universiti Sains Malaysia, School of Medical Sciences, Department of Haematology, 16150, Kubang Kerian, Kelantan, Malaysia.

View Article and Find Full Text PDF

Download full-text PDF

Source
August 2015

Multiplex amplification refractory mutation system (MARMS) for the detection of β-globin gene mutations among the transfusion-dependent β-thalassemia Malay patients in Kelantan, Northeast of Peninsular Malaysia.

Am J Blood Res 2014 5;4(1):33-40. Epub 2014 Sep 5.

Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia Malaysia.

The aim of this study was to adapt MARMS with some modifications to detect beta mutation in our cohort of thalassemia patients. We focused only on transfusion-dependent thalassemia Malay patients, the predominant ethnic group (95%) in the Kelantanese population. Eight mutations were identified in 46 out of 48 (95.83%) beta thalassemia alleles. Most of the patients (54.2%) were compound heterozygous with co-inheritance Cd 26 (G>A). The frequencies of spectrum beta chain mutation among these patients are presented in Table 2. Among the transfusion dependent beta thalassemia Malay patients studied, 26 patients were found to be compound heterozygous and the main alleles were Cd 26 (G>A). Compound heterozygous mutation of Cd 26 (G>A) and IVS 1-5 (G>C) were 12 (46.2%), Cd 26 (G>A) and Cd 41/42 (TTCT) were 9 (34.6%), Cd 26 (G>A) and IVS 1-1 (G>C) were 2 (7.7%) respectively. Meanwhile the minority were made of a single compound heterozygous of Cd 26 (G>A) and Cd 71/72, Cd 26 (>A) and Cd 17 (A>T), Cd 26 (G>A) and -28 (G>A) respectively. Twenty out of forty six patients were shown to have homozygous of IVS 1-5 (G>C) were 2 (10.0%), Cd 26 (G>A) were 15 (75.0%), Cd 19 (A>G) were 1 (5.0%), and IVS 1-1 (G>T) were 2 (10.0%). The beta chain mutations among the Kelantanese Malays followed closely the distribution of beta chain mutations among the Thais and the Malays of the Southern Thailand. The G-C transition at position 5 of the IVS 1-5 mutation was predominant among the Malay patients. In conclusion, this method has successfully identified the mutation spectrum in our cohort of transfusion-dependent beta thalassemia patients, and this method is equally effective in screening for mutation among thalassemia patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165115PMC
September 2014

Low level of TERC gene amplification between chronic myeloid leukaemia patients resistant and respond to imatinib mesylate treatment.

Asian Pac J Cancer Prev 2014 ;15(4):1863-9

Human Genome Center, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia E-mail :

The amplification of telomerase component (TERC) gene could play an important role in generation and treatment of haematological malignancies. This present study was aimed to investigate copy number amplification status of TERC gene in chronic myeloid leukaemia (CML) patients who were being treated with imatinib mesylate (IM). Genomic DNA was extracted from peripheral blood of CML-IM Resistant (n=63), CML-IM Respond (n=63) and healthy individuals (n=30). TERC gene copy number predicted (CNP) and copy number calculated (CNC) were determined based on Taqman® Copy Number Assay. Fluorescence in situ hybridization (FISH) analysis was performed to confirm the normal signal pattern in C4 (calibrator) for TERC gene. Nine of CML patients showed TERC gene amplification (CNP=3), others had 2 CNP. A total of 17 CML patients expressed CNC>2.31 and the rest had 2.31>CNC>1.5. TERC gene CNP value in healthy individuals was 2 and their CNC value showed in range 1.59-2.31. The average CNC TERC gene copy number was 2.07, 1.99 and 1.94 in CML- IM Resistant patients, CML-IM Respond and healthy groups, respectively. No significant difference of TERC gene amplification observed between CML-IM Resistant and CML-IM Respond patients. Low levels of TERC gene amplification might not have a huge impact in haematological disorders especially in terms of resistance towards IM treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7314/apjcp.2014.15.4.1863DOI Listing
November 2014

HOXA4 gene promoter hypermethylation as an epigenetic mechanism mediating resistance to imatinib mesylate in chronic myeloid leukemia patients.

Biomed Res Int 2013 26;2013:129715. Epub 2012 Dec 26.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus 16150 Kubang Kerian, Kelantan, Malaysia.

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients has emerged as a significant clinical problem. The observation that increased epigenetic silencing of potential tumor suppressor genes correlates with disease progression in some CML patients treated with IM suggests a relationship between epigenetic silencing and resistance development. We hypothesize that promoter hypermethylation of HOXA4 could be an epigenetic mechanism mediating IM resistance in CML patients. Thus a study was undertaken to investigate the promoter hypermethylation status of HOXA4 in CML patients on IM treatment and to determine its role in mediating resistance to IM. Genomic DNA was extracted from peripheral blood samples of 95 CML patients (38 good responders and 57 resistant) and 12 normal controls. All samples were bisulfite treated and analysed by methylation-specific high-resolution melt analysis. Compared to the good responders, the HOXA4 hypermethylation level was significantly higher (P = 0.002) in IM-resistant CML patients. On comparing the risk, HOXA4 hypermethylation was associated with a higher risk for IM resistance (OR 4.658; 95% CI, 1.673-12.971; P = 0.003). Thus, it is reasonable to suggest that promoter hypermethylation of HOXA4 gene could be an epigenetic mechanism mediating IM resistance in CML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2013/129715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591123PMC
September 2013

Mutation spectrum of dystrophin gene in malaysian patients with Duchenne/Becker muscular dystrophy.

J Neurogenet 2013 Jun 26;27(1-2):11-5. Epub 2013 Feb 26.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, USM Health Campus, Kelantan, Malaysia.

We undertook the clinical feature examination and dystrophin analysis using multiplex ligation-dependent probe amplification (MLPA) and direct DNA sequencing of selected exons in a cohort of 35 Malaysian Duchenne/Becker muscular dystrophy (DMD/BMD) patients. We found 27 patients with deletions of one or more exons, 2 patients with one exon duplication, 2 patients with nucleotide deletion, and 4 patients with nonsense mutations (including 1 patient with two nonsense mutations in the same exon). Although most cases showed compliance to the reading frame rule, we found two unrelated DMD patients with an in-frame deletion of the gene. Two novel mutations have been detected in the Dystrophin gene and our results were compatible with other studies where the majority of the mutations (62.8%) are located in the distal hotspot. However, the frequency of the mutations in our patient varied as compared with those found in other populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/01677063.2012.762580DOI Listing
June 2013

Genetic aberrations in childhood acute lymphoblastic leukaemia: application of high-density single nucleotide polymorphism array.

Authors:
Sarina Sulong

Malays J Med Sci 2010 Jul;17(3):5-12

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Screening of the entire human genome using high-density single nucleotide polymorphism array (SNPA) has become a powerful technique used in cancer genetics and population genetics studies. The GeneChip® Mapping Array, introduced by Affymetrix, is one SNPA platform utilised for genotyping studies. This GeneChip system allows researchers to gain a comprehensive view of cancer biology on a single platform for the quantification of chromosomal amplifications, deletions, and loss of heterozygosity or for allelic imbalance studies. Importantly, this array analysis has the potential to reveal novel genetic findings involved in the multistep development of cancer. Given the importance of genetic factors in leukaemogenesis and the usefulness of screening the whole genome, SNPA analysis has been utilised in many studies to characterise genetic aberrations in childhood acute lymphoblastic leukaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216177PMC
July 2010

A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups.

Blood 2009 Jan 6;113(1):100-7. Epub 2008 Oct 6.

Northern Institute for Cancer Research, Newcastle University, Queen Victoria Road, Newcastle upon Tyne, UK.

Inactivation of the tumor suppressor gene, CDKN2A, can occur by deletion, methylation, or mutation. We assessed the principal mode of inactivation in childhood acute lymphoblastic leukemia (ALL) and frequency in biologically relevant subgroups. Mutation or methylation was rare, whereas genomic deletion occurred in 21% of B-cell precursor ALL and 50% of T-ALL patients. Single nucleotide polymorphism arrays revealed copy number neutral (CNN) loss of heterozygosity (LOH) in 8% of patients. Array-based comparative genomic hybridization demonstrated that the mean size of deletions was 14.8 Mb and biallelic deletions composed a large and small deletion (mean sizes, 23.3 Mb and 1.4 Mb). Among 86 patients, only 2 small deletions were below the resolution of detection by fluorescence in situ hybridization. Patients with high hyperdiploidy, ETV6-RUNX1, or 11q23/MLL rearrangements had low rates of deletion (11%, 15%, 13%), whereas patients with t(9;22), t(1;19), TLX3, or TLX1 rearrangements had higher frequencies (61%, 42%, 78%, and 89%). In conclusion, CDKN2A deletion is a significant secondary abnormality in childhood ALL strongly correlated with phenotype and genotype. The variation in the incidence of CDKN2A deletions by cytogenetic subgroup may explain its inconsistent association with outcome. CNN LOH without apparent CDKN2A inactivation suggests the presence of other relevant genes in this region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2008-07-166801DOI Listing
January 2009

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

Telomerase activity in Malaysian patients with central nervous system tumors.

Southeast Asian J Trop Med Public Health 2003 Dec;34(4):872-6

Human Genome Center, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Telomerase, the enzyme that stabilizes telomere length is reactivated with almost all cancer types, and may be a useful diagnostic marker for malignancy. Telomerase activity has been detected in germ line cells and most cancer cells, whereas most normal somatic cells have no clearly detectable telomerase activity. In our study, we aim to detect telomerase activity in 20 human central nervous system tumors from Malaysian patients. Telomerase activity was detected based on a highly sensitive procedure consisting of a CHAPS detergent-based extraction from frozen tissues and a PCR-based telomeric repeat amplification protocol (TRAP) using a TRAPEZE Telomerase Detection Kit (Intergen, Co). Telomerase activity was considered positive when a ladder of products was observed starting at 50bp, with 6bp increments. The activity was detected in 30% of the samples analysed, included glioblastoma multiforme, meduloblastoma, paraganglioma and oligodendroglioma. The result of Fisher's exact test indicated that there was a significant association between telomerase activity status with tumor grade (p=0.003). These results suggest that telomerase activity may be an important marker for tumor malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2003

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