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Ravindran Ankathil Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia Abstract: 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. Keywords: leukemia, ABCB1 polymorphisms, chemotherapy response, survival

What is known and objective 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. Methods We genotyped 215 Malaysian patients with CML (comprising of two groups with 108 IM resistant and 107 IM responsive) for polymorphisms of ABCC1 (2012G>T and 2168G>A) and ABCC2 (-24C>T, 1249G>A and 3972C>T) genes. Genotype, allele and haplotype frequencies were compared between two groups of patients. Patients with CML were further stratified according to their clinical response to IM into those having cytogenetics and molecular responses, and the associations with genotypes were evaluated. Results and discussion We observed no significant differences in the distribution of any of the tested genotypes between the investigated groups. However, on evaluating the risk association, ABCC2 T-24G1249T3972 haplotype was found to be associated with IM resistance ( P = 0·046). These results suggest that haplotype variants -24T and 3972T might be associated with lower expression of ABCC2 protein and reduced transport activity and hence might be contributing to development of IM resistance. What is new and conclusion Our results suggest the ABCC2 T-24G1249T3972 haplotype was associated with imatinib resistance. However, the evidence is as yet insufficient to establish this haplotype as a predictive biomarker for response to the drug. [ABSTRACT FROM AUTHOR]

Background: Fragile X Syndrome (FXS) is the most prevalent inherited cause of mental retardation. The prevalence of FXS in males and females are approximately 1 in 4000 and 1 in 8000 respectively. It is caused by CGG repeat instability in the FMR1 gene, located on chromosome Xq27.3. Normal individuals have CGG repeats ranging from 5 to 53. In premutation carriers, the CGG repeats range from 60 to 200 and shall be more than 200 repeats for full mutation patients. FXS patients have variable clinical features and because of that, an accurate clinical diagnosis is always a problem. Currently, Cytogenetic, PCR and Southern Blot Techniques are widely used for diagnosis of FXS. Case Report: Here we report a pair of brothers suspected to be FXS patients with similar clinical features. Peripheral blood was collected from both brothers and was subjected to cytogenetics and molecular analysis involving PCR, Southern blot and methylation specific PCR (MSPCR) analysis. However, the Cytogenetic result for the younger brother did not show the fragile site at Xq27.3 of the X chromosome while the molecular result was confirmatory for full mutation of FXS. Conversely, the elder brother showed confirmatory results for FXS in both Cytogenetic and molecular analysis. However, the result showed a mosaic pattern (full mutation and pre mutation FMR1 allele) which was confirmed by Southern blot and MSPCR analysis. Conclusion: We therefore conclude that elder brother confirms for Fragile X mosaic and younger brother for Fragile X full mutation. From the result, Cytogenetic analysis alone cannot be dependable for the confirmatory diagnosis of FXS. [ABSTRACT FROM AUTHOR]

Down Syndrome (DS) is associated with an increased incidence of malignancies, especially leukaemias. We came across 8 DS children presenting with malignancies and having trisomy 21 as the sole cytogenetic abnormality. Of these 8 DS cases, 4 presented with acute lymphocytic leukaemia, 2 with acute myeloid leukaemia and one case each with Hodgkin's disease and Wilms' tumour. There are contradictory reports regarding the distribution of myeloid versus lymphoid malignancies in DS children and their response to therapy. The exact mechanism by which patients with DS are predisposed to develop malignancies is unclear. However, presence of the extra chromosome no. 21 is presumed to disrupt the genetic balance which increases generalized susceptibility to genetic and environmental trauma. Furthermore, an increased methotrexate toxicity observed in these patients should also be taken into consideration in designing treatment for DS children with malignancies. [ABSTRACT FROM AUTHOR]

Objective: To identify the different types of chromosome abnormalities in AML patients, to correlate these abnormalities with the AML subtypes and to determine the diagnostic and prognostic significance of these chromosome abnormalities. Design: A cross-sectional study. Materials and Methods: Cytogenetic investigations are undertaken routinely for diagnostic workup of AML patients at Hospital Universiti Sains Malaysia (HUSM). During the period from 2003 to 2006, bone marrow samples of 104 AML patients were analyzed at Human Genome Center, HUSM, for the presence of specific and non specific numerical and structural chromosome abnormalities. Results: Out of 104 samples analyzed cytogenetically, 54 (52%) showed normal karyotypes, 30 (29%) showed abnormal karyotypes and 20 (19%) failed to give satisfactory chromosome preparations. FAB subtype specific as well as nonspecific chromosome abnormalities were observed. In few cases which failed to give satisfactory cytogenetic results, molecular genetic analysis could provide data on the underlying molecular genetic alteration. Conclusion: Through cytogenetic analysis, both specific chromosome abnormalities associated with specific FAB subtypes of AML as well as other random chromosome abnormalities present in the leukemic cells was detected. Thus, cytogenetic analysis is important for diagnostic and prognostic workup of AML patients. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM), a clonal B-cell neoplasia, is an incurable and heterogeneous disease where survival ranges from a few months to more than 10 years. The clinical heterogeneity of MM arises from multiple genomic events that result in tumour development and progression. Recurring genomic abnormalities including cytogenetic abnormalities, gene mutations and abnormal gene expression profiles in myeloma cells have a strong prognostic power. With the advancement in technologies and the development of novel drugs, the prognostic factors and treatment paradigms of MM have been fast evolving over the past few years. Following the introduction of new highthroughput cytogenomic technologies such as array comparative genome hybridisation (aCGH) or single nucleotide polymorphism array (SNP array) and molecular techniques such as gene expression profiling (GEP) and massively parallel genomic sequencing, the prediction of survival in MM no longer solely depends on conventional cytogenetics and interphase fluorescence in situ hybridisation (iFISH) analysis findings. These new technologies enable screening for all possible chromosomal aberrations and other genomic alterations, identifying each aberration on a case-bycase basis and discovering new aberrations that are relevant in unraveling the tumor cells' complex biology. This in turn allows a better understanding of the disease complexity and heterogeneity. The objective of this review on the genetic architecture of MM is to discuss the latest developments on the cytogenetic/cytogenomic-based risk classification of MM that are currently in use and their prognostic implications.

Congenital leukaemia (CL) is an exceptionally uncommon hematologic malignancy originating intrauterine and is typically associated with an unfavourable prognosis. The present case is a seven-day-old Malay baby girl who presented with mild fever and hepatosplenomegaly. She was initially treated as neonatal sepsis however subsequent investigations with bone marrow, trephine biopsy and immunophenotyping were consistent with B acute lymphoblastic leukaemia. The peripheral blood smear showed the presence of 90% blast cells. Cytogenetically, she harboured an unusual complex karyotype, 46,XX,der(5) t(5;15)(p15;q15),del(7)(q33q35)/47,idem,+2.ish t(5;15)(wcp15+)+22(wcp22+).  This rare case with extremely atypical cytogenetic findings is being brought to light since the patient responded favourably to the standard chemotherapy Interfant 06 protocol, during which she obtained many episodes of remission, and she still survives after three years of treatment. Despite that, she carries del(7), which is normally associated with adverse outcomes in myeloid disorders, but not in lymphoid disorders; the existence of t(5;15)(p15;q15) could be the element that contributes to her fortunate outcome. Although trisomy 22 is identified as a clonal abnormality, its significance in her case and lymphoid disorders remains unknown and requires further investigation., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ankathil et al.)

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., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ankathil et al.)