ABCB1 genetic variants in leukemias: current insights into treatment outcomes

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 singlenucleotide 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

Data quality related to ungroupable cases : A pilot study for pre-implementation of casemix system in Hospital Universiti Sains Malaysia

Universiti Sains Malaysia (USM) as a premier university in Malaysia awarded an APEX (Accelerated Programme for Excellence) status has given an autonomy and flexibility in administration and access to additional funding from the government that the university heavily committed with a long term objective to transform the university into a centre of excellence at par with top universities of the world. Decision of using UNU-CBG Grouper as the grouping tool in Hospital USM (HUSM), the second oldest teaching hospital in Malaysia is the brilliant step to implement the casemix system as one of the initiative to improve quality and efficiency of its services. Project collaboration between HUSM and United Nations University-International Institute for Global Health and International Centre for Casemix and Clinical Coding of National University of Malaysia has developed a three year programme to gradually implement casemix system in the hospital. A pilot study was carried out to assess the quality of coding system currently practice at the Patient Record Unit, HUSM. Methods: All in-patient medical records for patients discharged in 2009 and 2010 were reviewed and selected for the pilot study. Six trained coders coded the diagnosis using ICD1 0 and procedures using ICD9-CM classifications. Those coded data set were exported into UNU-CBG Grouper for patient grouping process. In UNU-CBGs the first level of classification is Casemix Main Group (CMG) and the second level with higher degree of granularity is Case-Based Group (CBG). Results: A total of 43, 273 medical records contained adequate information to be grouped using the UNUCBG Groupers. This represents 60.6% of the total discharges for the two years period. 60% were female. Most the patients were of younger age group with 29.7% below the age of 20 years, 21.2% between the age of 21-30 years and only 14.5% are above 60years. A total of 1,806 (4.2%) discharges were ungroupable. Common reasons for ungroupable are coding errors of principle diagnosis (49.7%), no birth weight for babies (33.5%), coding errors for deliveries (7.9%) and wrong gender (5.5%). High percentage of invalid principle code was due to the technical error (50.2%) in assigning the ICD-10 codes where coders were mistakenly encode an extra digit or incomplete code or wrong character listed within the ICD-1 0 Classification System. Conclusions: Although the rate of ungroupable is quite low, more efforts should be made to train the coders on the coding rules as required by the casemix groupers. The outcome of this pilot study showed that the medical records system in the hospital could be further enhanced by ensuring that the minimum data set for casemix system is captured routinely. Therefore, would achieve the inspiration of cqsemix principle as an initiative to improve quality and efficiency of !'lealthcare services in HUSI'y1 and thus, support the University for the APEX agenda

Imatinab mesylate treatment in Chronic Myeloid Leukemia (CML)- understanding the fundamental pharmacokinetic and pharmacogenetic mechanisms for variation in response

Although lmatinib mesylate (IM) is the gold standard drug for Chronic Myeloid Leukemia (CML) treatment, resistance to IM emerges in a significant number of patients. Resistance could be due to several factors. Pharmacokinetic variability as a result of genetic polymorphisms in IM metabolizing genes could be a potential factor. This study was undertaken to investigate the genotype frequencies and the impact of ORM1 520G>A, PXR 1792A>G, CAR 540C>T, CYP3A4 878T>C and CYP3A5 6986A>G polymorphisms towards CML susceptibility risk and IM response. A total of 540 subjects (270 CML patients and 250 normal healthy controls) have been recruited in this study. Genotyping was performed and the association between allelic variants and CML susceptibility risk and response to IM treatment were assessed by means of odds ratio (OR) with 95% confident interval s calculated by logistic regression. Results showed that PXR 1792A>G, CAR 540C>T and CYP3A5 6986A>G were significantly associated with IM responses and CAR 540C>T, CYP3A4 878T>C and CYP3A5 6986A>G were significantly associated with CML susceptibility risk. Further study should be done on a larger scale to validate whether this polymorphism can be used as a predictive biomarker for identifying resistance development among CML patients undergoing IM treatment

Identification predisposition genotypes that contribute to colorectal cancer susceptibility in Malaysia

Although this is the first comprehensive study on the association of SNP in xenobiotic metabolizing and DNA damage repair genes in Malaysian population, the study'has been limited by the small sample size due to short ·1 time period and budget. Because of this, large number of samples could not be included. For the same reason, the frequency of variant allele observed for certain SNPs were too small or sometimes nii which must have resulted in inadequate in statistical power. During risk analysis of combination of genotypes, the infrequent presence or rarity of at-risk genotype or allele, for some of the '<Ombination SNPs studied resulted in deriving risk association values with high ORs values, but with extremely wide range of 95% confidence intervals. Such combinations genotypes were not considered as high risk predisposition genotypes despite the high ORs obtained. I Malaysian population comprises 3 maJor ethnic groups; Malay, Chinese and Indian with a ratio of approximately 60:30:10, respectively. Different the ethnic races have different genetic background. The difference in genetic background of the study subjects which comprised these 3 ethnic races was not taken into account and this was another limitation. A stratified analysis based on.ethnicity with equal number of the study subjects in each ethnic group, could have given better results with adequate power. The study subjects in this study were recruited from differing collaborating hospitals in Malaysia. From some of the hospitals, it was difficult and unable to get many of the epidemiological and clinicopathological details of the case subjects. So the interaction of confotinding factors like lifestyle habits (smoking, alcohol consumption), dietary habits etc with the SNP included ~n the study could not be examined

Risk modification of colorectal cancer susceptibility by interleukin-8 -251T>A polymorphism in Malaysians

AIM: To investigate the allele and genotype frequencies and associated risk of interleukin (IL )-8 -251T>A polymorphism on colorectal cancer (CRC) susceptibility risk. METHODS: Peripheral blood samples of 255 normal controls and 255 clinically and histopathologically confirmed CRC patients were genotyped for IL-8 -251T>A polymorphism employing allele-specific polymerase chain reaction. The relative association of variant allele and genotypes with CRC susceptibility risk was determined by calculating the odds ratios (ORs). Corresponding χ 2 tests on the CRC patients and controls were carried out and 95% confidence intervals (CIs) were determined using Fisher’s exact test. The allele frequencies and its risk association were calculated using FAMHAP, haplotype association analysis software. RESULTS: On comparing the frequencies of genotypes of patients and controls, the homozygous variant AA was significantly higher in CRC patients (P = 0.002) compared to controls. Investigation on the association of the polymorphic genotypes with CRC susceptibility risk, showed that the homozygous variant IL-8 -251AA had a significantly increased risk with OR 3.600 (95% CI: 1.550-8.481, P = 0.001). In the case of allele frequencies, variant allele A of IL-8 -251 showed a significantly increased risk of CRC predisposition with OR 1.32 (95% CI: 1.03-1.69, P = 0.003). CONCLUSION: Variant allele and genotype of IL-8 (-251 T>A) was significantly associated with CRC susceptibility risk and could be considered as a high-risk variant for CRC predisposition

XPC Lys939Gln polymorphism, smoking and risk of sporadic colorectal cancer among Malaysians

AIM: 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. METHODS: Peripheral blood samples of 510 study subjects (255 CRC patients, 255 controls)were collected. DNA was extracted and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. The association between polymorphic genotype and CRC predisposition was determined using the OR and 95%CI. RESULTS: The frequency of the homozygous variant (Gln/Gln) genotype was significantly higher in cases compared with controls (16.0% vs 10.2%, P = 0.049). The Gln/Gln genotype of XPC showed a significantly higher association with the risk of CRC (OR = 1.884; 95%CI: 1.082-3.277; P = 0.025). In the case of allele frequencies, variant allele C was associated with a significantly increased risk of CRC (OR = 1.375; 95%CI: 1.050-1.802; P = 0.020). Moreover, the risk was markedly higher for those who were carriers of the Gln/Gln variant genotype and were also cigarette smokers (OR = 3.409; 95%CI: 1.061-10.949; P = 0.032). CONCLUSION: The XPC Gln/Gln genotype alone and in combination with smoking increases the risk of CRC among Malaysians

Polymorphism Thr241Met of the XRCC3 Gene and Lack of Association with Colorectal Cancer Susceptibility Risk among Malaysian Population: A Preliminary Report

The genesis of colorectal cancer (CRC) involves a series of steps in which environmental and/or endogenous carcinogens interact with genetic factors and induce or promote cancer development. Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity and may be associated with a high risk of developing cancer. Studies on the association between DNA repair gene polymorphisms and CRC appear to be limited and nil from Malaysia. Objective: To examine the polymorphism at codon 241 of the X-Ray Cross Complementing group 3 (XRCC3) in 118 CRC cases and 118 normal controls and to investigate the associated risk of this polymorphism for CRC susceptibility. Material and Method: Peripheral blood from the study subjects were collected in EDTA tubes, genomic DNA extracted and XRCC3 Thr241Met genotyped by using PCR-RFLP technique using Nla III restriction enzyme. The resulting genotypes were categorized into wildtype homozygous (Thr/Thr), heterozygous (Thr/Met) and homozygous variant (Met/Met). Results and conclusion: The distribution of genotypes (Thr/Thr, Thr/Met and Met/Met) among CRC cases (83%, 16%, 1% respectively) was not significantly different from those among controls (79%, 21%, 0% respectively). On examining the association between the variant genotypes and CRC risk, the variant genotype either single or in combination did not show significant association with CRC susceptibility risk suggesting that the XRCC3 codon 241 polymorphism does not convey moderate increase in susceptibility to CRC in Malaysian population. Lack of association could be attributed to the small sample size, interaction of other polymorphic DNA repair genes and also low frequency of variant allele for the polymorphism studied in this population

Polymorphism in the Tumor Necrosis Factor alpha promoter region and its Influence on Colorectal Cancer Predispositiom risk in Malaysian Population

Objective: A case control study was designed to investigate the TNF-,1 -308 G>A polymorphism allele frequencies and to determine the influence of the polymorphic gcnot.ype on sporadic CRC susceptibility risk in Malaysian population. Material. and Method!: Peripheral blood samples of 164 normal controls and 161 clinically and histopathologically con­firmed CRC patients were genotyped for TNF-u -308 G>A polymorphism employing allele specific PCR. The relative associa­tions of various genotypes with CRC susceptibility risk was determined by calculating Odds Ratios. Corresponding chi-square tests on the CRC patients and controls were carried out and 95% confidence interval (95% CI) were determined using Fisher e,acts tests. Results: On comparing the frequencies of genotypes of patients and controls, the homozygous ,·ariant AA was significantly higher in CRC patients (p = 0.030) compared to controls. On investigating the association of the polymorphic genotypes with CRC susceptibility risk, the homozygous variant TNF-a -308 AA showed significantly increased risk with OR 2.5842. Conclusion: Our results suggest that, pol) morphic genotJpe of inflammation response gene TNF-a is significantly associat­ed with CRC susceptibility risk and could be considered as a high risk variant for CRC predisposition

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so