Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia

Despite imatinib mesylate (IM) being the frontline drug for successful treatment of chronic myeloid leukaemia (CML), a significant proportion of CML patients on IM therapy develop resistance and attain poor outcome. The objective of the present study was to investigate the contribution of selecte...

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Main Author:	Ismail, Siti Mariam
Format:	Thesis
Language:	English
Published:	2023
Subjects:	RC Internal medicine
Online Access:	http://eprints.usm.my/58908/1/SITI%20MARIAM%20ISMAIL%20-FINAL%20THESIS%20S-UD000420%28R%29%2024%20pages.pdf
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spelling	my-usm-ep.589082023-08-06T07:23:09Z Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia 2023-04 Ismail, Siti Mariam RC Internal medicine Despite imatinib mesylate (IM) being the frontline drug for successful treatment of chronic myeloid leukaemia (CML), a significant proportion of CML patients on IM therapy develop resistance and attain poor outcome. The objective of the present study was to investigate the contribution of selected polymorphisms of VEGFA (+936 C>T and -634 G>C), VEGFR2 (1192 C>T, ivs25-29 G>A and 1416 T>A), BIM (intron 2 deletion and c465 C>T), TP53 mutation at exon 8 and additional chromosome abnormalities (ACAs) in modulating IM treatment response and disease progression in 249 Malaysia CML patients undergoing IM treatemnt. For this study, CML patients comprising of 127 IM resistant and 122 IM good response were recriuted. For VEGFA +936 C>T and -634 G>C, VEGFR2 1192 C>T, ivs25-29 G>A and 1416 T>A and BIM c465 C>T Polymerase Chain Reaction- Restriction Enzyme Fragment Length Polymorphims (PCR – RFLP) was employed and allele specific – PCR (AS – PCR) for BIM intron 2 deletion polymorphims, TP53 mutation at exon 8 was investigated using PCR amplification followed by DNA sequencing. ACAs were investigated employing standard cytogenetic procedures and FISH. With regard to VEGFA, both the SNPs +936 C>T and -634 G>C showed significant lower risk for the development of resistance. For the homozygous variant (TT) +936 C>T, of showed OR: 0.11 (95 % CI = 0.02 – 0.56, p = 0.008) and CC of the -634 G>C showed OR: 0.17 (95 % CI = 0.07 – 0.41, p = 0.001). The C allele of -634 G>C was also significantly associated with lower risk for development of IM resistance (OR: 0.49, 95 % CI = 0.34 – 0.71, p = 0.001). In the case of VEGFR2, ivs25-29 G>A SNP, only homozygous variant (AA) showed significant lower risk association with development of resistance with OR, 0.17 (95 % CI = 0.04 – 0.84, p = 0.029). For SNP of 1416 T>A, the heterozygous variant (TA) and homozygous variant (AA) showed significant lower risk for development of resistance (OR: 0.25, 95 % CI: 0.11 – 0.59, p = 0.002 for heterozygous variant and OR: 0.27, 95 % CI = 0.12 – 0.62, p = 0.002 for homozygous variant respectively). In the case of TP53 exon 8 and BIM intron 2 deletion, all study subjects showed wildtype genotype with no mutation in exon 8 and no deletion detected in intron 2. For BIM c465 C>T, the heterozygous variant (CT) and dominant genetic model CT + TT (OR: 2.14, 95 % CI = 1.24 – 3.67, p = 0.006 and OR: 1.99, 95 % CI = 1.19 – 3.34, p = 0.009) and variant allele T (OR: 1.57, 95 % CI = 1.03 – 2.39, p = 0.036) showed higher risk for the development of resistance to IM. ACAs were detected in 40/ 249 patients (16.1 %). For determining the prognosis impact of ACAs, these 40 patients were categorized to those with Ph+/ ACAs and Ph-/ ACAs and further stratified into four groups based on the type of abnormalities. Patients with group 1 and group 2 abnormalities showed comparatively better prognosis while patients with group 3 and 4 abnormalities showed higher risk for disease progression. Novel ACAs consisting of rearrangements involving chromosomes 11 and 12 were found to lead to myeloid BP. Stratification based on individual ACAs found to have differential prognostic impact and might be a potential risk predictive system to prognosticate and guide treatment of CML patients. These findings from the present study demonstrated obvious relationships of host genetic and tumour genomic factors with IM treatment response and disease progression These genetic factors could be potential biomarkers to predict IM treatment response and disease progression in Malaysian CML patients. 2023-04 Thesis http://eprints.usm.my/58908/ http://eprints.usm.my/58908/1/SITI%20MARIAM%20ISMAIL%20-FINAL%20THESIS%20S-UD000420%28R%29%2024%20pages.pdf application/pdf en public phd doctoral Universiti Sains Malaysia Pusat Pengajian Sains Perubatan
institution	Universiti Sains Malaysia
collection	USM Institutional Repository
language	English
topic	RC Internal medicine
spellingShingle	RC Internal medicine Ismail, Siti Mariam Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia
description	Despite imatinib mesylate (IM) being the frontline drug for successful treatment of chronic myeloid leukaemia (CML), a significant proportion of CML patients on IM therapy develop resistance and attain poor outcome. The objective of the present study was to investigate the contribution of selected polymorphisms of VEGFA (+936 C>T and -634 G>C), VEGFR2 (1192 C>T, ivs25-29 G>A and 1416 T>A), BIM (intron 2 deletion and c465 C>T), TP53 mutation at exon 8 and additional chromosome abnormalities (ACAs) in modulating IM treatment response and disease progression in 249 Malaysia CML patients undergoing IM treatemnt. For this study, CML patients comprising of 127 IM resistant and 122 IM good response were recriuted. For VEGFA +936 C>T and -634 G>C, VEGFR2 1192 C>T, ivs25-29 G>A and 1416 T>A and BIM c465 C>T Polymerase Chain Reaction- Restriction Enzyme Fragment Length Polymorphims (PCR – RFLP) was employed and allele specific – PCR (AS – PCR) for BIM intron 2 deletion polymorphims, TP53 mutation at exon 8 was investigated using PCR amplification followed by DNA sequencing. ACAs were investigated employing standard cytogenetic procedures and FISH. With regard to VEGFA, both the SNPs +936 C>T and -634 G>C showed significant lower risk for the development of resistance. For the homozygous variant (TT) +936 C>T, of showed OR: 0.11 (95 % CI = 0.02 – 0.56, p = 0.008) and CC of the -634 G>C showed OR: 0.17 (95 % CI = 0.07 – 0.41, p = 0.001). The C allele of -634 G>C was also significantly associated with lower risk for development of IM resistance (OR: 0.49, 95 % CI = 0.34 – 0.71, p = 0.001). In the case of VEGFR2, ivs25-29 G>A SNP, only homozygous variant (AA) showed significant lower risk association with development of resistance with OR, 0.17 (95 % CI = 0.04 – 0.84, p = 0.029). For SNP of 1416 T>A, the heterozygous variant (TA) and homozygous variant (AA) showed significant lower risk for development of resistance (OR: 0.25, 95 % CI: 0.11 – 0.59, p = 0.002 for heterozygous variant and OR: 0.27, 95 % CI = 0.12 – 0.62, p = 0.002 for homozygous variant respectively). In the case of TP53 exon 8 and BIM intron 2 deletion, all study subjects showed wildtype genotype with no mutation in exon 8 and no deletion detected in intron 2. For BIM c465 C>T, the heterozygous variant (CT) and dominant genetic model CT + TT (OR: 2.14, 95 % CI = 1.24 – 3.67, p = 0.006 and OR: 1.99, 95 % CI = 1.19 – 3.34, p = 0.009) and variant allele T (OR: 1.57, 95 % CI = 1.03 – 2.39, p = 0.036) showed higher risk for the development of resistance to IM. ACAs were detected in 40/ 249 patients (16.1 %). For determining the prognosis impact of ACAs, these 40 patients were categorized to those with Ph+/ ACAs and Ph-/ ACAs and further stratified into four groups based on the type of abnormalities. Patients with group 1 and group 2 abnormalities showed comparatively better prognosis while patients with group 3 and 4 abnormalities showed higher risk for disease progression. Novel ACAs consisting of rearrangements involving chromosomes 11 and 12 were found to lead to myeloid BP. Stratification based on individual ACAs found to have differential prognostic impact and might be a potential risk predictive system to prognosticate and guide treatment of CML patients. These findings from the present study demonstrated obvious relationships of host genetic and tumour genomic factors with IM treatment response and disease progression These genetic factors could be potential biomarkers to predict IM treatment response and disease progression in Malaysian CML patients.
format	Thesis
qualification_name	Doctor of Philosophy (PhD.)
qualification_level	Doctorate
author	Ismail, Siti Mariam
author_facet	Ismail, Siti Mariam
author_sort	Ismail, Siti Mariam
title	Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia
title_short	Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia
title_full	Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia
title_fullStr	Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia
title_full_unstemmed	Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia
title_sort	genetic determinants excluding gbcr::abl mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in malaysia
granting_institution	Universiti Sains Malaysia
granting_department	Pusat Pengajian Sains Perubatan
publishDate	2023
url	http://eprints.usm.my/58908/1/SITI%20MARIAM%20ISMAIL%20-FINAL%20THESIS%20S-UD000420%28R%29%2024%20pages.pdf
_version_	1776101241480282112

Genetic determinants excluding GBCR::ABL mutations of imatinib mesylate therapy response among chronic myeloid leukaemia patients in Malaysia

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