Ismail, Siti Mariam
(2023)
Genetic determinants excluding GBCR::ABL
mutations of imatinib mesylate therapy
response among chronic myeloid
leukaemia patients in Malaysia.
PhD thesis, Universiti Sains Malaysia.
Abstract
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.
Actions (login required)
 |
View Item |
