Masters Degrees (Haematological Pathology)

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Browsing Masters Degrees (Haematological Pathology) by Author "De Long, Chantal"

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    Imatinib resistance : the role of pharmacogenetic variability in a South African chronic myeloid leukemia cohort
    (Stellenbosch : Stellenbosch University, 2023-03) De Long, Chantal; Swanepoel, Carmen; Stellenbosch University. Faculty of Medicine and Health Science. Dept. of Pathology. Haematological Pathology.
    ENGLISH SUMMARY: Drug-resistant cancers are often associated with poor patient outcomes and the underlying mechanism is poorly understood. Chronic Myeloid Leukemia (CML) serves as a disease model for studying cancer drug resistance, specifically to Imatinib, a tyrosine kinase inhibitor. Approximately 20-30% of patients become resistant to Imatinib. Variability in patient drug response could be due to single nucleotide variants (SNVs) in genes that encode for Imatinib-metabolizing enzymes and transporters. The overall aim of the present study is to determine whether selected SNVs located within genes CYP3A4/3A5, SLCO1A2, SLC22A4, and SLC22A1 that encode selected drug transporters (Cytochrome P450, OATP1A2, OCTN1, hOCT1), respectively, contribute to an alternative mechanism leading to Imatinib resistance in a South African cohort. A maximum of 45 samples from Imatinib-resistant CML patients were analysed along with 44 non-resistant CML patients (controls). The selected SNVs were analysed using PCR-based genotyping assays. Baseline allelic and genotypic frequencies within our CML cohort was determined and compared between Imatinib good responders and Imatinib resistant groups. In our study we observed that there were differences in allele frequencies for the following SNVs in genes SLC22A4, SLCO1A2, CYP3A4 and CYP3A5 when compared to the global/African frequencies. Furthermore, obtained results showed that the observed and expected genotype frequencies were comparable for genes SLC22A1, SLC22A4, and SLCO1A2, however, our observed genotype frequencies were different from the expected genotype frequencies for the following genes SLCO1A2, CYP3A4 and CYP3A5. Interesting findings include, the rs35191146 (ATG>AT: delG) that was linked poor Imatinib treatment outcome, however, the simultaneous presence of rs628031 (A>G: M408V) circumvented this effect. All patients within our cohort have both Met420 and Met408Val. Another interesting finding is the coincidental finding of variants SLC22A4 rs11568500 (c.616_617delinsCC), and SLC22A1 rs35191146 (c.1258_1260delATG and g.160139876_160139883delGTAAGTTG), which would be explored in future studies. Even though the selected SNVs do not affect Imatinib resistance in our cohort, our study to the best of our knowledge is the only study to determine baseline allelic and genotypic frequencies for CML patients treated with Imatinib in South Africa. Therefore, the data obtained from our study can serve as a useful tool to further investigate the pharmacogenetic variability in South Africa. In conclusion, our study adds to the body of knowledge out there related to SNV and its potential clinical relevance related to imatinib resistance especially within our diverse African cohort. This in turn highlights the need for future studies focusing on larger cohorts, with a larger selection of SNVs at more health care institutions across South Africa.