Displaying publications 21 - 40 of 51 in total

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  1. Fulltext Two cases of deletion 5p syndrome: one with paternal involvement and another with atypical presentation
    Azman BZ, Akhir SM, Zilfalil BA, Ankathil R
    Singapore Med J, 2008 Apr;49(4):e98-e100.
    PMID: 18418516
    We report two cases of deletion 5p or cri du chat syndrome (CdCS) with different presentations and risks of transmission: one case with paternal chromosome 5 involvement and another, a de novo case with atypical clinical presentation. Cytogenetic analysis was performed on the two cases and their parents. GTG-banded karyotype analysis of Cases 1 and 2 revealed abnormal 46,XY,del(5)(p13-15) male karyotypes. For Case 1, the mother showed normal female karyotype while the father showed an abnormal karyotype involving a balanced translocation 46,XY,t(5;10)(p13;p15). For Case 2, however, both parents showed a normal karyotype pattern. In Case 1, the clinical features, particularly the distinct facial phenotype in combination with a characteristic cat-like cry and hypotonia, aided in the diagnosis at birth and the karyotype analysis was resolutive. The boy in Case 2 presented with atypical clinical features. Even though this patient had multiple syndromic features, the typical high pitched cat-like cry was not prominent. Instead, the patient manifested persistent stridor (from day three of life), which might have prevented the clinician from suspecting CdCS at birth. However, when this patient was presented at seven months of age for cytogenetic analysis, a confirmatory diagnosis of CdCS was established. For children with congenital abnormalities, an early clinical diagnosis confirmed through cytogenetic and molecular investigations, is important for providing personalised diagnostic and prognostic evaluation, and also for genetic counselling on the reproductive risk, particularly for patients with parental chromosome translocation involvement.
  2. Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients
    Au A, Aziz Baba A, Goh AS, Wahid Fadilah SA, Teh A, Rosline H, et al.
    Biomed Pharmacother, 2014 Apr;68(3):343-9.
    PMID: 24581936 DOI: 10.1016/j.biopha.2014.01.009
    The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.
  3. Germline mutation and protein expression analysis of mismatch repair genes MSH6 and PMS2 in Malaysian Lynch syndrome patients
    Zahary MN, Kaur G, Hassan MR, Sidek AS, Singh H, Yeh LY, et al.
    Int J Colorectal Dis, 2014 Feb;29(2):261-2.
    PMID: 24072394 DOI: 10.1007/s00384-013-1770-1
  4. A new method for FMR1 gene methylation screening by multiplex methylation-specific real-time polymerase chain reaction
    Elias MH, Ankathil R, Salmi AR, Sudhikaran W, Limprasert P, Zilfalil BA
    Genet Test Mol Biomarkers, 2011 Jun;15(6):387-93.
    PMID: 21329465 DOI: 10.1089/gtmb.2010.0191
    Fragile X Syndrome (FXS) is the most common form of inherited mental retardation in men. It is caused by abnormalities in the FMR1 gene that are associated with CGG repeat expansion and the hypermethylation status of its promoter. Methylated alleles lead to transcriptional inhibition and consequent loss of Fragile X Mental Retardation Protein. Chemical modification of cytosine to uracil by bisulfite treatment has proved to be an attractive method for DNA methylation studies that precludes labor-intensive Southern blot analysis, which is the gold standard test for FXS. In this report, bisulfite-treated DNA samples were amplified using real-time multiplex methylation-specific polymerase chain reaction followed by melting curve analysis. Our results show that all control samples with known CGG repeat numbers and methylation statuses were correctly diagnosed. The samples from 43 male patients were also successfully diagnosed, which were in complete agreement with the results of Southern blotting. By such means, 39 patients were found to have an unmethylated allele; 3, a fully mutated allele; and 1, both methylated and unmethylated alleles, thus implying a diagnosis of mosaicism. In conclusion, we find our method to be convenient for screening a large number of male patients with FXS, because it is rapid and easy to perform, especially when there is a low quantity of DNA that must be sensitively and accurately assayed.
  5. Fulltext Somatic copy-neutral loss of heterozygosity and copy number abnormalities in Malaysian sporadic colorectal carcinoma patients
    Yam YY, Hoh BP, Othman NH, Hassan S, Yahya MM, Zakaria Z, et al.
    Genet. Mol. Res., 2013;12(1):319-27.
    PMID: 23420356 DOI: 10.4238/2013.February.7.1
    Colorectal cancer is one of the most common cancers in many countries, including Malaysia. The accumulation of genomic alterations is an important feature of colorectal carcinogenesis. A better understanding of the molecular events underlying the stages of colorectal carcinogenesis might be helpful in the detection and management of the disease. We used a commercially available single-nucleotide polymorphism genotyping array to detect both copy number abnormalities (CNAs) and copy-neutral loss of heterozygosity (LOH) in sporadic colorectal carcinomas. Matched tumor and normal tissues of 13 colorectal carcinomas (Dukes' stages A-D) were analyzed using a 250K single nucleotide polymorphism array. An additional assay was performed to determine the microsatellite instability status by using the National Cancer Institute-recommended BAT-26 panel. In general, copy number gain (92.3%) was most common, followed by copy number loss (53.8%) and copy-neutral LOH (46.2%). Frequent CNAs of gains and losses were observed on chromosomes 7p, 8, 13q, 17p, 18q, and 20q, and copy-neutral LOH was observed on chromosomes 2, 6, 12, 13q, 14q, 17, 20p, 19q, and 22q. Even though genomic alterations are associated with colorectal cancer progression, our results showed that DNA CNAs and copy-neutral LOH do not reflect disease progression in at least 50% tumors. Copy-neutral LOH was observed in both early and advanced tumors, which favors the involvement of these genomic alterations in the early stages of tumor development.
  6. Fulltext Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients
    Zahary MN, Kaur G, Abu Hassan MR, Singh H, Naik VR, Ankathil R
    World J Gastroenterol, 2012 Feb 28;18(8):814-20.
    PMID: 22371642 DOI: 10.3748/wjg.v18.i8.814
    To investigate the protein expression profile of mismatch repair (MMR) genes in suspected cases of Lynch syndrome and to characterize the associated germline mutations.
  7. FAS c.-671A>G polymorphism and cervical cancer risk: a case-control study and meta-analysis
    Tan SC, Ismail MP, Duski DR, Othman NH, Ankathil R
    Cancer Genet, 2017 02;211:18-25.
    PMID: 28279307 DOI: 10.1016/j.cancergen.2017.01.004
    This study aimed to investigate the association between FAS c.-671A>G polymorphism and cervical cancer risk in a case-control setting, followed by a meta-analysis of the published literatures. The case-control study involved genotyping of the polymorphism in 185 histopathologically confirmed cervical cancer patients and 209 cancer-free female controls utilizing PCR-RFLP technique, followed by logistic regression analyses. Meta-analysis was then conducted under homozygous, heterozygous, dominant, recessive and allele contrast models to combine data from 12 studies which consisted of 2798 cases and 3039 controls. Our case-control analysis revealed a significant association of the variant allele (G) and the homozygous variant genotype (GG) of the FAS polymorphism with an increased risk of cervical cancer. Subgroup analysis by ethnicity further confirmed the risk association in Malays (P  0.05). However, results of meta-analysis suggested a lack of association between the polymorphism and cervical cancer risk in all the five genetic models analyzed. In conclusion, while the FAS c.-671A>G polymorphism may serve as a biomarker for cervical cancer risk prediction among the Malays, there is a limited usability of the polymorphism as a cervical cancer risk biomarker in other populations.
  8. microRNA expression and recurrence risk prediction in Triple Negative Breast Cancer patients
    AbdulAziz A, MdSalleh M, Mohamad I, Bhavaraju V, Gan S, Ankathil R
    Ann Oncol, 2017 Oct;28 Suppl 9:ix79.
    PMID: 32120675 DOI: 10.1093/annonc/mdx697.022
  9. Fulltext Prognostic Implications of DNA Repair, Ploidy and Telomerase in the Malignant Transformation Risk Assessment of Leukoplakia
    Thomas G, Tr S, George S P, Somanathan T, Sarojam S, Krishnankutti N, et al.
    Asian Pac J Cancer Prev, 2020 Feb 01;21(2):309-316.
    PMID: 32102504 DOI: 10.31557/APJCP.2020.21.2.309
    BACKGROUND: Although leukoplakia shows a higher risk for malignant transformation to oral cancer, currently there are no clinically relevant biomarker which can predict the potentially high risk leukoplakia. This study aimed to investigate the genetic alterations such as DNA ploidy, telomerase expression and DNA repair capacity as predictive markers of malignant transformation risk of leukoplakia.

    METHODS: The study was initiated in September 2005 and patients were followed up to March 2014. Two hundred patients with oral leukoplakia, 100 patients with oral cancer and 100 healthy, age and sex matched adults with normal oral mucosa as controls were recruited. The DNA ploidy content was measured by high resolution flow cytometry, level of telomerase expression was identified by TRAP assay and intrinsic DNA repair capacity was measured by mutagen induced chromosome sensitivity assay of cultured peripheral blood lymphocytes. The Chi-square test or Fisher's Exact test was used for comparison of categorical variables between biomarkers. A p value less than or equal to 0.05 was considered as statistically significant. Analysis was performed with SPSS software version 16. Logistic regression was used to find the association between the dependent and three independent variables.

    RESULTS: There was significant difference in the distribution of ploidy status, telomerase activity and DNA repair capacity among control, leukoplakia and oral cancer group (p<0.001). When the molecular markers were compared with histological grading of leukoplakia, both DNA ploidy analysis and telomerase activity showed statistical significance (p<0.001). Both aneuploidy and telomerase positivity was found to coincide with high-risk sites of leukoplakia and were statistically significant (p.

  10. The differential metabolite profiles of acute lymphoblastic leukaemic patients treated with 6-mercaptopurine using untargeted metabolomics approach
    Bannur Z, Teh LK, Hennesy T, Rosli WR, Mohamad N, Nasir A, et al.
    Clin Biochem, 2014 Apr;47(6):427-31.
    PMID: 24582698 DOI: 10.1016/j.clinbiochem.2014.02.013
    Acute lymphoblastic leukaemia (ALL) has posed challenges to the clinician due to variable patients' responses and late diagnosis. With the advance in metabolomics, early detection and personalised treatment are possible.
  11. Fulltext Hyperdiploid Multiple Myeloma with Novel Complex Structural Chromosome Abnormalities Associated with Poor Prognosis : A Rare Case Report
    Ankathil R, Foong E, Siti-Mariam I, Norhidayah R, Nazihah MY, Sangeetha V, et al.
    Int J Hematol Oncol Stem Cell Res, 2021 Jul 01;15(3):199-205.
    PMID: 35083001 DOI: 10.18502/ijhoscr.v15i3.6852
    Hyperdiploid multiple myeloma (MM) is associated with better prognosis and non-hyperdiploid subtype is associated with variable to adverse prognosis based on the nature of karyotype abnormality.  Rarely exceptions to this hyperdiploid and non-hyperdiploid divisions do exist in a minority. We report an adult male MM patient who showed hyperdiploid karyotype with few novel complex abnormalities and who showed poor clinical outcome. Conventional cytogenetic analysis carried out in 22 GTG banded metaphases showed 53,Y,der(X)t(X;22)(q27;q11.2),+3,+5,+6,+9,+11,+15,der(17)ins(17;1;3)(q11.2;?;?),der(17)ins(17;1;3)(q11.2;?;?),+19,-22,+mar karyotype pattern in 15 metaphases whereas 7 metaphases showed 46,XY karyotype  pattern.  Interphase FISH revealed biallelic del(13q14) and del(17p13) but no translocations involving the 14q32 region. Through Spectral karyotyping FISH, the origin of complex abnormalities involving der(17) chromosome,  translocation t(X;22), and marker chromosome could be clearly delineated. Although the present case showed hyperdiploid karyotype, he showed an adverse prognosis probably due to the co-existence of high risk and complex abnormalities and expired 5 months after initial diagnosis despite standard treatment given.
  12. Fulltext Genetic Association of CYP1B1 4326 C>G Polymorphism with Disease-Free Survival in TNBC Patients Undergoing TAC Chemotherapy Regimen
    Abdul Aziz AA, Md Salleh MS, Yahya MM, Zakaria AD, Ankathil R
    Asian Pac J Cancer Prev, 2021 Apr 01;22(4):1319-1324.
    PMID: 33906328 DOI: 10.31557/APJCP.2021.22.4.1319
    BACKGROUND: Triple negative breast cancer (TNBC) which is treated with taxane, adriamycin and cyclophosphamide (TAC) chemotherapy regimen show variation in treatment response. CYP1B1 4326 C>G polymorphism has been implicated in contributing to the differences in treatment response in various types of cancers.

    AIM: The objective of the present study was to investigate whether this polymorphism modulate the risk of disease recurrence in TNBC patients undergoing TAC chemotherapy regimen.

    METHODS: Blood samples of 76 immunohistochemistry confirmed TNBC patients were recruited. The genotyping of CYP1B1 4326 C>G polymorphism was carried out using PCR-RFLP technique. The genotype patterns were categorized into homozygous wildtype, heterozygous and homozygous variant. Kaplan-Meier analysis followed by Cox proportional hazard regression model were performed to evaluate the TNBC patients' recurrence risk.

    RESULTS: Out of 76 TNBC patients, 25 (33.0%) showed disease recurrence after one-year evaluation. Kaplan Meier analysis showed that TNBC patients who are carriers of CYP1B1 4326 GG variant genotypes (37.0%) had a significantly lower probability of disease-free rates as compared to TNBC patients who are carriers of CYP1B1 4326 CC/CG genotypes (71.0%). Univariate and multivariate Cox analysis demonstrated that TNBC patients who carried CYP1B1 4326 GG variant genotype had a significantly higher risk of recurrence with HR: 2.50 and HR: 4.18 respectively, even after adjustment as compared to TNBC patients who were carriers of CYP1B1 4326 CC and CG genotypes.

    CONCLUSION: Our results demonstrate the potential use of CYP1B1 4325 GG variant genotype as a candidate biomarker in predicting risk of recurrence in TNBC patients undergoing TAC chemotherapy regimen.

  13. Identification of Optimal Reference Genes for Normalization of RT-qPCR Data in Cancerous and Non-Cancerous Tissues of Human Uterine Cervix
    Tan SC, Ismail MP, Duski DR, Othman NH, Bhavaraju VM, Ankathil R
    Cancer Invest, 2017 Mar 16;35(3):163-173.
    PMID: 28301252 DOI: 10.1080/07357907.2017.1278767
    This study aimed to identify the most stably expressed reference genes from a panel of 32 candidate genes for normalization of reverse transcription-quantitative real-time polymerase chain reaction data in cancerous and non-cancerous tissues of human uterine cervix. Overall, PUM1, YWHAZ, and RPLP0 were identified as the most stably expressed genes in paired cancerous and non-cancerous tissues. The results were further stratified by the state of malignancy of the tissues, histopathological type of the cancer, and the human papillomavirus-type.
  14. Fulltext Chromosomal abnormalities and reproductive outcome in Malaysian couples with miscarriages
    Pal S, Ma SO, Norhasimah M, Suhaida MA, Siti Mariam I, Ankathil R, et al.
    Singapore Med J, 2009 Oct;50(10):1008-12.
    PMID: 19907893
    This study was done to determine the prevalence of chromosomal abnormalities and the subsequent reproductive outcome in couples who had two or more miscarriages.
  15. Polymorphisms of cell cycle regulator genes CCND1 G870A and TP53 C215G: Association with colorectal cancer susceptibility risk in a Malaysian population
    Zahary MN, Ahmad Aizat AA, Kaur G, Yeong Yeh L, Mazuwin M, Ankathil R
    Oncol Lett, 2015 Nov;10(5):3216-3222.
    PMID: 26722315
    Colorectal cancer (CRC) occurs as a more common sporadic form and a less common familial form. Our earlier analysis of germline mutations of mismatch repair genes confirmed only 32% of familial CRC cases as Lynch syndrome cases. It was hypothesized that the remaining familial aggregation may be 'polygenic' due to single nucleotide polymorphisms (SNPs) of low penetrance genes involved in cancer predisposition pathways, such as cell cycle regulation and apoptosis pathways. The current case-control study involving 104 CRC patients (52 sporadic and 52 familial) and 104 normal healthy controls investigated the contribution of the SNPs cyclin D1 (CCND1) G870A and tumor protein p53 (TP53) C215G in modulating familial and sporadic CRC susceptibility risk. DNA was extracted from peripheral blood and the polymorphisms were genotyped by employing a polymerase chain reaction-restriction fragment length polymorphism method. The association between these polymorphisms and CRC susceptibility risk was calculated using a binary logistic regression analysis and deriving odds ratios (ORs). The A/A variant genotype of CCND1 and G/G variant genotype of TP53 exhibited a significantly greater association with the risk of sporadic CRC [CCND1: OR, 3.471; 95% confidence interval (CI), 1.443-8.350; P=0.005. TP53: OR, 2.829; CI, 1.119-7.152; P=0.026] as well as familial CRC susceptibility (CCND1: OR, 3.086; CI, 1.270-7.497; P=0.019. TP53: OR, 3.048; CI, 1.147-8.097; P=0.030). The results suggest a potential role of the SNPs CCND1 G870A and TP53 C215G in the modulation of sporadic and familial CRC susceptibility risk.
  16. Chromosome Translocation t(6; 14) With Different Phenotypes and Segregation Patterns: A Report of Two Cases
    Ankathil R, Zakaria WNA, Hamid MR, Ismail SM, Mohd Yunus N, Annuar AA, et al.
    Cureus, 2024 Sep;16(9):e68402.
    PMID: 39360045 DOI: 10.7759/cureus.68402
    Chromosomal rearrangement can disrupt gene function by interfering with coding sequences or their regulatory regions. The breakpoint in these rearrangements can pinpoint the disease-related gene's location. This paper presents two rare cases of chromosomal rearrangement involving chromosome 6 (6p24-25) and chromosome 14 (14q22-23). The first case involves a girl with hearing impairment, inheriting a balanced translocation of chromosomes 6 and 14 from her father. The second case describes a dysmorphic baby boy with congenital bilateral choanal atresia and a tertiary trisomy, involving a translocation between chromosome 6 (6p24) and chromosome 14 (14q22), resulting in a derivative chromosome (14) in addition to the normal complement of chromosomes 6 and 14. The boy's mother had a history of four recurrent miscarriages. However, the origin of this tertiary trisomy in the second case presented could not be delineated because the parents did not consent and declined their blood samples for karyotyping. Parental karyotyping and chromosomal analysis are crucial for investigating recurrent miscarriages, identifying genetic causes, guiding reproductive decisions, and improving successful pregnancy outcomes for affected couples.
  17. Fulltext Prevalence and type distribution of human papillomavirus (HPV) in Malaysian women with and without cervical cancer: an updated estimate
    Tan SC, Ismail MP, Duski DR, Othman NH, Ankathil R
    Biosci Rep, 2018 Apr 27;38(2).
    PMID: 29487170 DOI: 10.1042/BSR20171268
    Information on the prevalence and type distribution of human papillomavirus (HPV) among Malaysian women is currently limited. The present study therefore aimed to provide an updated estimate on the prevalence and type distribution of HPV among Malaysian women with and without cervical cancer. Total DNA was isolated from the cervical cell specimens of 185 histopathologically confirmed cervical cancer patients and 209 cancer-free healthy females who were tested negative in a recent Pap test. Viral-specific DNA was subsequently amplified with biotinylated primers and hybridized to HPV type-specific probes via a proprietary "flow-through hybridization" process for determination of HPV genotype. It was demonstrated that 83.2% of the cervical cancer patients and none (0.0%) of the cancer-free females were positive for HPV infection. Among HPV-positive subjects, 14 different viral genotypes were observed, namely HPV16, 18, 31, 33, 35, 45, 52, 53, 58, 66/68, 73, 81, 82, and 84/26. A total of 91.6% of the HPV-positive subjects had single-type HPV infections and the remaining 8.4% were simultaneously infected by two HPV genotypes. The most common HPV infections found were HPV16 (35.7%), HPV18 (26.0%), HPV58 (9.1%), and HPV33 (7.1%) single-type infections, followed by HPV16 + HPV18 co-infections (5.2%). The study has successfully provided an updated estimate on the prevalence and type distribution of HPV among Malaysian women with and without cervical cancer. These findings could contribute valuable information for appraisal of the impact and cost-effectiveness of prophylactic HPV vaccines in the Malaysian population.
  18. Fulltext Association of ABCG2 Polymorphisms on Triple Negative Breast Cancer (TNBC) Susceptibility Risk
    Hao Ing Y, Md Salleh MS, Yahya MM, Ankathil R, Abdul Aziz AA
    Asian Pac J Cancer Prev, 2023 Nov 01;24(11):3891-3897.
    PMID: 38019248 DOI: 10.31557/APJCP.2023.24.11.3891
    OBJECTIVE: The aim of this study was to elucidate the association of ATP-binding cassette super-family G member 2 (ABCG2) gene polymorphisms with individual susceptibility to Triple Negative Breast Cancer (TNBC) as well as clinicopathological variables in TNBC patients. Two common polymorphisms in Asian population, ABCG2 34 G>A and 421 C>A was selected in this study.

    METHODS: Blood samples were collected from 75 TNBC patients and 83 controls. Genomic DNA was extracted from blood samples and the SNP genotyping was performed by using PCR-RFLP technique. The genotypes were characterized and grouped into homozygous wildtype, heterozygote and homozygous variant based on the band size. The result was subjected to statistical analysis.

    RESULTS: The A allele and AA genotype of ABCG2 421 C>A had OR of 3.011 (p=0.003, 95% CI: 1.417-6.398) and 9.042 (p=0.011, 95% CI: 1.640-49.837), to develop advanced staging carcinoma respectively. The AA genotype of ABCG2 421 C>A polymorphism was also associated with metaplastic and medullary carcinoma with an OR of 6.429 (p=0.018, 95% CI: 1.373-30.109). A significant association was also found in haplotype 34G/421A of ABCG2 with advanced cancer staging as well as metaplastic and medullary carcinoma with OR of 2.347 (p=0.032, 95% CI: 1.010-5.560) and 2.546 (p=0.008, 95% CI: 1.005-6.447), respectively.  Conclusion: The present study suggests that ABCG2 421 C>A polymorphism was associated with metaplastic and medullary histology and advanced cancer staging in TNBC patients.

  19. BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome
    Elias MH, Baba AA, Azlan H, Rosline H, Sim GA, Padmini M, et al.
    Leuk. Res., 2014 Apr;38(4):454-9.
    PMID: 24456693 DOI: 10.1016/j.leukres.2013.12.025
    Discovery of imatinib mesylate (IM) as the targeted BCR-ABL protein tyrosine kinase inhibitor (TKI) has resulted in its use as the frontline therapy for chronic myeloid leukemia (CML) across the world. Although high response rates are observed in CML patients who receive IM treatment, a significant number of patients develop resistance to IM. Resistance to IM in patients has been associated with a heterogeneous array of mechanisms of which point mutations within the ABL tyrosine kinase domain (TKD) are the frequently documented. The types and frequencies of mutations reported in different population studies have shown wide variability. We screened 125 Malaysian CML patients on IM therapy who showed either TKI refractory or resistance to IM to investigate the frequency and pattern of BCR-ABL kinase domain mutations among Malaysian CML patients undergoing IM therapy and to determine the clinical significance. Mutational screening using denaturing high performance liquid chromatography (dHPLC) followed by DNA sequencing was performed on 125 IM resistant Malaysian CML patients. Mutations were detected in 28 patients (22.4%). Fifteen different types of mutations (T315I, E255K, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation. The data generated from clinical and molecular parameters studied were correlated with the survival of CML patients. Patients with Y253H, M351T and E355G TKD mutations showed poorer prognosis compared to those without mutation. Interestingly, when the prognostic impact of the observed mutations was compared inter-individually, E355G and Y253H mutations were associated with more adverse prognosis and shorter survival (P=0.025 and 0.005 respectively) than T315I mutation. Results suggest that apart from those mutations occurring in the three crucial regions (catalytic domain, P-loop and activation-loop), other rare mutations also may have high impact in the development of resistance and adverse prognosis. Presence of mutations in different regions of BCR-ABL TKD leads to different levels of resistance and early detection of emerging mutant clones may help in decision making for alternative treatment. Serial monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatments in such CML patients.
  20. The functional -94 insertion/deletion ATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer
    Mohd Suzairi MS, Tan SC, Ahmad Aizat AA, Mohd Aminudin M, Siti Nurfatimah MS, Andee ZD, et al.
    Cancer Epidemiol, 2013 Oct;37(5):634-8.
    PMID: 23806437 DOI: 10.1016/j.canep.2013.05.007
    To investigate the allele and genotype frequencies of NFKB1 -94 ins/del ATTG (rs28720239) polymorphism and to evaluate the association between the polymorphism and colorectal cancer (CRC) risk in Malaysian population.
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