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  1. Ankathil R
    Pharmgenomics Pers Med, 2017;10:169-181.
    PMID: 28546766 DOI: 10.2147/PGPM.S105208
    Despite improvements in treatment of different types of leukemia, not all patients respond optimally for a particular treatment. Some treatments will work better for some, while being harmful or ineffective for others. This is due to genetic variation in the form of single-nucleotide polymorphisms (SNPs) that affect gene expression or function and cause inherited interindividual differences in the metabolism and disposition of drugs. Drug transporters are one of the determinants governing the pharmacokinetic profile of chemotherapeutic drugs. The ABCB1 transporter gene transports a wide range of drugs, including drugs used in leukemia treatment. Polymorphisms in the ABCB1 gene do affect intrinsic resistance and pharmacokinetics of several drugs used in leukemia treatment protocols and thereby affect the efficacy of treatment and event-free survival. This review focuses on the impact of three commonly occurring SNPs (1236C>T, 2677G>T/A, and 3435C>T) of ABCB1 on treatment response of various types of leukemia. From the literature available, some of the genotypes and haplotypes of these SNPs have been found to be potential determinants of interindividual variability in drug disposition and pharmacologic response in different types of leukemia. However, due to inconsistencies in the results observed across the studies, additional studies, considering novel genomic methodologies, comprehensive definition of clinical phenotypes, adequate sample size, and uniformity in all the confounding factors, are warranted.
  2. Tan SC, Ankathil R
    Tumour Biol., 2015 Sep;36(9):6633-44.
    PMID: 26242271 DOI: 10.1007/s13277-015-3868-2
    Cervical cancer is a common malignancy which poses a significant health burden among women, especially those living in the developing countries. Although human papillomavirus (HPV) infection has been unequivocally implicated in the etiopathogenesis of the cancer, it alone is not adequate to contribute to the malignant transformation of cervical cells. Most HPV infections regress spontaneously, and only a small proportion of women have persistent infections which eventually lead to malignancy. This suggests that interplays between HPV infection and other cofactors certainly exist during the process of cervical carcinogenesis, which synergistically contribute to the differential susceptibility of an individual to the malignancy. Undoubtedly, host genetic factors represent a major element involved in such a synergistic interaction, and accumulating evidence suggests that polymorphisms in apoptosis-related genes play an important role in the genetic susceptibility to cervical cancer. This review consolidates the recent literatures on the role of common polymorphisms in apoptosis-related genes in genetic susceptibility to cervical cancer.
  3. Rashid RA, Ankathil R
    Malays J Pathol, 2020 Aug;42(2):171-185.
    PMID: 32860369
    Gene therapy is a method of treatment of disease aimed at its molecular level. The progress of gene therapy, however, was as promising as it was tardy mainly due to the limitations in the resources and financial part of its development as well as owing to the rarity of most diseases it can offer its benefits to. The methods of gene therapy can vary depending on factors such as the physiology of tissue of interest, affinity of vectors to a certain type of cells, depth and accessibility of the tissue of interest, and size of the gene to be replaced or edited. The concept behind gene therapy has inspired scientists and clinicians alike leading to a rapid expansion of its clinical utility that has become so widespread to not only include diseases of monogenic origin, but also polygenic diseases, albeit not so commonly. This article delves into notable success stories of gene therapy which has been regarded as the beacon of medical novelty expected to blossom in the near future to provide a holistic, targeted, precise, and individualistic personalised-medicine as well as laying out the future hopes of gene therapy in the treatment of debilitating diseases such as solid tumours, AIDS, Tuberculosis, Diabetes Mellitus, psychiatric illnesses, which are still at a standstill, from a gene therapy point of view.
  4. Norhasimah, M.M., Ahmad Tarmizi, A.B., Azman, B.A., Zilfalil, B.A., Ankathil, R.
    MyJurnal
    Generally, the karyotype profile of Down Syndrome has been reported to be full trisomy 21 in 92% of patients, mosaic trisomy 21 in 4% of patients and translocation involving chromosome 21 in 4% of patients in most of the population groups worldwide. But, karyotype analysis of 149 DS patients at the Human Genome Center, USM, during the past five years revealed that free trisomy accounted for 94.6%, mosaic trisomy 21 for 4.7% and translocation involving chromosome 21 in 0.7% of the Down Syndrome etiology in North East Malaysian population, indicating a low frequency of translocation DS in this region. Here, we report one case of translocation Down Syndrome encountered during karyotype analysis of 149 DS cases. Karyotype showed a robertsonian translocation where an entire extra chromosome 21 was attached to the centromere of one of the chromosome 14, resulting in a derivative chromosome 14 with attached chromosome 21. Karyotype analysis of the parents revealed a normal 46,XY pattern for father and 46,XX pattern for mother indicating that this robertsonian translocation had arisen de novo either prior to or at conception.
  5. Au A, Baba AA, Azlan H, Norsa'adah B, Ankathil R
    J Clin Pharm Ther, 2014 Dec;39(6):685-90.
    PMID: 25060527 DOI: 10.1111/jcpt.12197
    The introduction and success of imatinib mesylate (IM) has brought about a paradigm shift in chronic myeloid leukaemia (CML) treatment. However, despite the high efficacy of IM, clinical resistance develops due to a heterogeneous array of mechanisms. Pharmacogenetic variability as a result of genetic polymorphisms could be one of the most important factors influencing resistance to IM. The aim of this study was to investigate the association between genetic variations in drug efflux transporter ABCC1 (MRP1) and ABCC2 (MRP2) genes and response to IM in patients with CML.
  6. Kannan TP, Hemlatha S, Ankathil R, Zilfalil BA
    Indian J Pediatr, 2009 Jul;76(7):745-6.
    PMID: 19475342 DOI: 10.1007/s12098-009-0158-2
    Complete trisomy 9 is a lethal diagnosis and most fetuses diagnosed thus die prenatally or during the early postnatal period and majority of such cases have been known to end in spontaneous abortion in the first trimester itself. One such rare survival of fetus ending in normal delivery and surviving until 20 days is reported here detailing the clinical manifestations of the child during the period of survival. The salient clinical features observed were small face, wide fontanel, prominent occiput, micrognathia, low set ears, upslanting palpebral fissures, high arched palate, short sternum, overlapping fingers, limited hip abduction, rocker bottom feet, heart murmurs and also webbed neck, characteristic of this trisomy 9 syndrome.
  7. Nair SV, Madhulaxmi, Thomas G, Ankathil R
    J Maxillofac Oral Surg, 2021 Sep;20(3):340-344.
    PMID: 34408360 DOI: 10.1007/s12663-020-01462-4
    Objective: In this article, we provide a gestalt idea about NGS technologies and their applications in cancer research and molecular diagnosis.

    Background: Next-generation sequencing (NGS) advancements like DNA sequencing and RNA sequencing allow uncovering of genomic, transcriptomic, and epigenomic scenes of individual malignant growths. An assortment of genomic abnormalities can be screened at the same time, for example common and uncommon variations, auxiliary variations like insertions and deletions, copy-number variation, and fusion transcripts.

    Conclusion: NGS innovations together with bioinformatics investigation, which extend our insight, are progressively used to analyze multiple genes in a cost-effective way and have been applied in examining clinical cancer samples and offering NGS-based molecular diagnosis.

    Application: NGS is progressively significant as a device for the diagnosis of cancers.

  8. Pal S, Siti MI, Ankathil R, Zilfalil BA
    Singapore Med J, 2007 May;48(5):e146-50.
    PMID: 17453088
    Patients with isochromosome 18q, a rare cytogenetic abnormality, also reported as Edwards syndrome, is the second most common autosomal trisomy. However, the phenotypic features and survival of these patients are not uniform and depend upon the portion of chromosomes getting duplicated or deleted. The survival of these children may be longer, hence a good cytogenetic diagnosis is a must. Morphological characteristics of isochromosome 18q are not yet fully delineated because of the rarity of the cases and as most cases are aborted medically or terminate spontaneously. We report two cases of isochromosome 18q, one male aged two years old and the other a male aged eight months old, and review the literature on this rare syndrome.
  9. Tan KL, Ankathil R, Gan SH
    J Chromatogr B Analyt Technol Biomed Life Sci, 2011 Nov 15;879(30):3583-91.
    PMID: 22000961 DOI: 10.1016/j.jchromb.2011.09.048
    We developed a simple and sensitive method for the simultaneous detection of imatinib mesylate (IM) and its active metabolite, N-desmethyl imatinib (M1), in human serum samples. Separation was successfully achieved using an Agilent(®) ZORBAX Eclipse plus C(18) reversed phase column (50 mm × 2.1 mm, i.d.; 1.8 μm) under isocratic mobile phase conditions consisting of acetonitrile: 0.02 M potassium dihydrogen phosphate with 0.2% triethylamine at pH 3 (25:75, v/v) and ultra-violet detection was achieved at 235 nm. Extraction of the target compounds was completed using 100% cold acetonitrile. Good linearities (r(2)>0.99) for both IM and M1 were achieved for the concentration ranges of 50-1800 ng/mL and 50-360 ng/mL, respectively. The detection limits were 20 ng/mL and 10 ng/mL for M1 and IM, respectively. The intra- and inter-day precisions were less than 1% with percent recoveries of more than 90%. The method was successfully applied to calculate the pharmacokinetic parameters of chronic myeloid leukemia patients receiving imatinib. The method is suitable to be routinely applied for determination of IM and M1 in serum.
  10. Makhtar SM, Husin A, Baba AA, Ankathil R
    J Genet, 2017 Sep;96(4):633-639.
    PMID: 28947711
    The detoxifying activity of glutathione S-transferases (GST) enzymes not only protect cells from the adverse effects of xenobiotics, but also alters the effectiveness of drugs in cancer cells, resulting in toxicity or drug resistance. In this study, we aimed to evaluate the association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with treatment response among Malaysian chronic myeloid leukaemia (CML) patients who everyday undergo 400 mg of imatinib mesylate (IM) therapy. Multiplex polymerase chain reaction (multiplex-PCR) was performed to detect GSTM1 and GSTT1 polymorphisms simultaneously and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to detect the GSTP1 Ile195Val polymorphism. On evaluating the association of the variant genotype with treatment outcome, heterozygous variant (AG) and homozygous variant (GG) of GSTP1 Ile105Val showed significantly a higher risk for the development of resistance to IM with OR: 1.951 (95% CI: 1.186-3.209, P = 0.009) and OR: 3.540 (95% CI: 1.305-9.606, P = 0.013), respectively. Likewise, GSTT1 null genotype was also associated with a significantly higher risk for the development of resistance to IM with OR = 1.664 (95% CI: 1.011-2.739, P = 0.045). Our results indicate the potential usefulness of GST polymorphism genotyping in predicting the IM treatment response among CML patients.
  11. Makhtar SM, Husin A, Baba AA, Ankathil R
    J Genet, 2018 Sep;97(4):835-842.
    PMID: 30262695
    Imatinib mesylate (IM), a well-established gold standard drug in the treatment of chronic myeloid leukaemia (CML), is a synthetic tyrosine kinase inhibitor. Despite excellent efficacy, a significant number of patients on IM therapy develop resistance to IM. Currently, great focus has been laid on the effect of interindividual pharmacogenetic variability on IM treatment responses. IM uptake is mediated by the hOCT1 protein encoded by the solute carrier 22 gene (SLC22A1). The current study investigated the impact of few single-nucleotide polymorphisms (SNPs) of SLC22A1 on mediating resistance and/or good response to IM among 278 Malaysian CML patients (146 IM-resistant group and 132 IM good response group) undergoing IM therapy on 400 mg daily. Our results showed that the allelic frequencies of heterozygous (CG) and homozygous variant (GG) genotypes of SLC22A1 C480G were significantly higher in the IM-resistant group compared with the IM good response group (41.8% versus 30.3% and 10.9% versus 4.5% with P values of 0.047 and 0.048, respectively). On evaluating the association of genotypes with risk of IM resistance development, heterozygous (CG) and homozygous (GG) variant genotypes showed significantly higher risk for developing resistance to IM treatment with odds ratio (OR): 1.901 (95% confidence interval (CI): 1.142-3.163, P = 0.013) and 3.324 (95% CI: 1.235-8.947, P = 0.017), respectively. Two SNPs and two insertions/deletions were detected in exon 7 of SLC22A1. For exon 7, 1222AA carriers together with the presence of both the 8-bp insertion and 3-bp deletion, and M420del alleles showed higher possibility of developing resistance towards IMtreatment. Our results warrant the need of genotyping this SNP in terms of modulating IM treatment in CML patients.
  12. Mustapha MA, Shahpudin SN, Aziz AA, Ankathil R
    World J Gastroenterol, 2012 Jun 7;18(21):2668-73.
    PMID: 22690076 DOI: 10.3748/wjg.v18.i21.2668
    To investigate the allele and genotype frequencies and associated risk of interleukin (IL)-8 -251T>A polymorphism on colorectal cancer (CRC) susceptibility risk.
  13. Ahmad Aizat AA, Siti Nurfatimah MS, Aminudin MM, Ankathil R
    World J Gastroenterol, 2013 Jun 21;19(23):3623-8.
    PMID: 23801864 DOI: 10.3748/wjg.v19.i23.3623
    To investigate the risk association of xeroderma pigmentosum group C (XPC) Lys939Gln polymorphism alone and in combination with cigarette smoking on colorectal cancer (CRC) predisposition.
  14. Elias MH, Azlan H, Sulong S, Baba AA, Ankathil R
    Cancer Rep (Hoboken), 2018 08;1(2):e1111.
    PMID: 32721103 DOI: 10.1002/cnr2.1111
    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.

  15. Ankathil R, Ismail SM, Mohd Yunus N, Sulong S, Husin A, Abdullah AD, et al.
    Malays J Pathol, 2020 Dec;42(3):307-321.
    PMID: 33361712
    Chronic myeloid leukaemia (CML) provides an illustrative disease model for both molecular pathogenesis of cancer and rational drug therapy. Imatinib mesylate (IM), a BCR-ABL1 targeted tyrosine kinase inhibitor (TKI) drug, is the first line gold standard drug for CML treatment. Conventional cytogenetic analysis (CCA) can identify the standard and variant Philadelphia (Ph) chromosome, and any additional complex chromosome abnormalities at diagnosis as well as during treatment course. Fluorescence in situ hybridization (FISH) is especially important for cells of CML patients with inadequate or inferior quality metaphases or those with variant Ph translocations. CCA in conjunction with FISH can serve as powerful tools in all phases of CML including the diagnosis, prognosis, risk stratification and monitoring of cytogenetic responses to treatment. Molecular techniques such as reverse transcriptase-polymerase chain reaction (RT-PCR) is used for the detection of BCR-ABL1 transcripts at diagnosis whereas quantitative reverse transcriptase-polymerase chain reaction (qRTPCR) is used at the time of diagnosis as well as during TKI therapy for the quantitation of BCR-ABL1 transcripts to evaluate the molecular response and minimal residual disease (MRD). Despite the excellent treatment results obtained after the introduction of TKI drugs, especially Imatinib mesylate (IM), resistance to TKIs develops in approximately 35% - 40% of CML patients on TKI therapy. Since point mutations in BCR-ABL1 are a common cause of IM resistance, mutation analysis is important in IM resistant patients. Mutations are reliably detected by nested PCR amplification of the translocated ABL1 kinase domain followed by direct sequencing of the entire amplified kinase domain. The objective of this review is to highlight the importance of regular and timely CCA, FISH analysis and molecular testing in the diagnosis, prognosis, assessment of therapeutic efficacy, evaluation of MRD and in the detection of BCR-ABL1 kinase mutations which cause therapeutic resistance in adult CML patients.
  16. Maddin N, Husin A, Gan SH, Aziz BA, Ankathil R
    Oncol Ther, 2016;4(2):303-314.
    PMID: 28261657 DOI: 10.1007/s40487-016-0035-x
    INTRODUCTION: Imatinib mesylate (IM), a selective inhibitor of the BCR-ABL tyrosine kinase, is a well-established first-line treatment for chronic myeloid leukemia (CML). IM is metabolized mainly by cytochrome P450 (CYP) in the liver, specifically the CYP3A4 and CYP3A5 enzymes. Polymorphisms in these genes can alter the enzyme activity of IM and may affect its response. In this study, the impact of two single-nucleotide polymorphisms (SNPs), CYP3A5*3 (6986A>G) and CYP3A4*18 (878T>C), on IM treatment response in CML patients (n = 270; 139 IM resistant and 131 IM good responders) was investigated.

    METHODS: Genotyping of CYP3A4*18 and CYP3A5*3 was performed using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and treatment response was assessed by means of odds ratio (OR) with 95% confidence intervals calculated by logistic regression.

    RESULTS: Our results indicated that CML patients carrying the heterozygous (AG) and homozygous variant (GG) genotype of CYP3A5*3 were associated with a significantly lower risk of acquiring resistance with OR 0.171; 95% CI: 0.090-0.324, p 

  17. Elias MH, Azlan H, Baba AA, Ankathil R
    PMID: 29669505 DOI: 10.2174/1871529X18666180419101416
    BACKGROUND: In exploring the cause of Imatinib Mesylate (IM) resistance among Chronic Myeloid Leukemia (CML) patients who do not harbor BCR-ABL dependent mechanism, BCR-ABL independent pathways are the most probable pathways that should be explored. In BCR-ABL independent pathway, SOCS1 plays an important role as it helps in regulating optimal JAK/STAT activity.

    OBJECTIVE: To identify the association of SOCS1 gene hypermethylation in mediating IM Resistance.

    METHOD: The SOCS1 promoter methylation level of 92 BCR-ABL non mutated IM resistant CML patients, 83 IM good response CML patients and 5 normal samples from healthy individuals were measured using Methylation Specific-High Resolution Melt (MS-HRM) analysis.

    RESULTS: Both primers used to amplify promoter region from -333 to -223 and from -332 to -188 showed less than 10% methylation in all CML and normal samples. Consequently, there was no significant difference in SOCS1 promoter methylation level between IM resistant and IM good response patients.

    CONCLUSION: SOCS1 promoter methylation level is not suitable to be used as one of the biomarkers for predicting the possibility of acquiring resistance among CML patients treated with IM.

  18. Abdul Aziz AA, Md Salleh MS, Ankathil R
    Int J Breast Cancer, 2020;2020:8424365.
    PMID: 32308997 DOI: 10.1155/2020/8424365
    Triple negative breast cancer (TNBC) is associated with aggressive tumour phenotype and early tumour relapse following diagnosis. Generally, clinicopathological features such as tumour size, patient's age at diagnosis, tumour histology subtypes, grade and stage, involvement of lymph nodes, and menopausal status are commonly used for predicting disease progression, prospects of recurrence, and treatment response. Prognostic value of clinicopathological features on Malaysian TNBC patients is limited. Thus, this study is aimed at investigating the association of clinicopathological features on disease-free survival (DFS) and overall survival (OS) of Malaysian TNBC patients undergoing TAC chemotherapy. Seventy-six (76) immunohistochemistry-confirmed TNBC patients were recruited. The clinicopathological features of TNBC patients were collected and recorded. Kaplan-Meier and log-rank followed by a Cox proportional hazard regression model were performed to evaluate the TNBC patients' survival. Out of 76 TNBC patients, 25 were chemoresistant and 51 were chemoresponders to the TAC chemotherapy regimen. The overall 5-year cumulative DFS and OS of TNBC patients were 63.5% and 76.3%, respectively. Multivariate Cox analysis demonstrated that medullary and metaplastic histology subtypes and positive axillary lymph node metastasis were significant prognostic factors associated with relapse with adjusted HR: 5.76, 95% CI: 2.35, 14.08 and adjusted HR: 3.55, 95% CI: 1.44, 8.74, respectively. Moreover, TNBC patients with medullary and metaplastic histology subtypes and positive axillary lymph node metastases had a higher risk to death than patients who had infiltrating ductal carcinoma and negative axillary lymph node metastasis (adjusted HR: 8.30, 95% CI: 2.38, 28.96 and adjusted HR: 6.12, 95% CI: 1.32, 28.42, respectively). Our results demonstrate the potential use of medullary and metaplastic histology subtype and positive axillary lymph node metastasis as a potential biomarker in predicting relapse and survival of the TNBC patients. This warrants further studies on intensification of chemotherapy and also identification and development of targeted therapy to reduce relapses and improve survival of TNBC patients.
  19. Ankathil R, Azlan H, Dzarr AA, Baba AA
    Pharmacogenomics, 2018 04;19(5):475-393.
    PMID: 29569526 DOI: 10.2217/pgs-2017-0193
    Despite the excellent efficacy and improved clinical responses obtained with imatinib mesylate (IM), development of resistance in a significant proportion of chronic myeloid leukemia (CML) patients on IM therapy have emerged as a challenging problem in clinical practice. Resistance to imatinib can be due to heterogeneous array of factors involving BCR/ABL-dependent and BCR/ABL-independent pathways. Although BCR/ABL mutation is the major contributory factor for IM resistance, reduced bio-availability of IM in leukemic cells is also an important pharmacokinetic factor that contributes to development of resistance to IM in CML patients. The contribution of polymorphisms of the pharmacogenes in relation to IM disposition and treatment outcomes have been studied by various research groups in numerous population cohorts. However, the conclusions arising from these studies have been highly inconsistent. This review encompasses an updated insight into the impact of pharmacogenetic variability on treatment response of IM in CML patients.
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