Imatinib resistance : the role of pharmacogenetic variability in a South African chronic myeloid leukemia cohort

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dc.contributor.advisorSwanepoel, Carmenen_ZA
dc.contributor.authorDe Long, Chantalen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Science. Dept. of Pathology. Haematological Pathology.en_ZA
dc.date.accessioned2023-03-06T10:10:37Z
dc.date.accessioned2023-05-18T07:14:35Z
dc.date.available2023-03-06T10:10:37Z
dc.date.available2023-05-18T07:14:35Z
dc.date.issued2023-03
dc.descriptionThesis (MMed)--Stellenbosch University, 2023.en_ZA
dc.description.abstractENGLISH 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.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Dwelmweerstandige kankers word dikwels geassosieer met swak pasientuitkomste en die onderliggende meganisme word swak verstaan. Chroniese Myeloiede Leukemie (CML) dien as 'n siektemodel vir die bestudering van kankermedisyneweerstandigheid, spesifiek teen Imatinib, 'n tirosienkinaseinhibeerder. Ongeveer 20-30% van pasiente word weerstand teen Imatinib. Veranderlikheid in pasient geneesmiddelreaksie kan te wyte wees aan enkelnukleotied variant (SNVs) in gene wat kodeer vir Imatinib-metaboliserende ensieme en vervoerders. Die oorhoofse doel van die huidige studie is om te bepaal of geselekteerde SNV's gelee binne gene CYP3A4/3A5, SLCO1A2, SLC22A4 en SLC22A1 wat onderskeidelik geselekteerde geneesmiddelvervoerders (Cytochrome P450, OATP1A2, OCTN1, hOCT1) kodeer, bydra tot 'n alternatiewe meganisme wat lei aan Imatinib-weerstand in 'n Suid-Afrikaanse kohort. 'n Maksimum van 45 monsters van Imatinib-weerstandige CML-pasiente is ontleed saam met 44 nie-weerstandige CML-pasiente (kontroles). Die geselekteerde SNVs is ontleed deur gebruik te maak van PCR-gebaseerde genotiperingstoetse. Basislyn alleliese en genotipiese frekwensies binne ons CMLkohort is bepaal en vergelyk tussen Imatinib goeie reageerders en Imatinibweerstandige groepe In ons studie het ons waargeneem dat daar verskille was in alleelfrekwensies vir die volgende SNV's in gene SLC22A4, SLCO1A2, CYP3A4 en CYP3A5 in vergelyking met die globale en Afrika-frekwensies. Verder, verkry resultate het getoon dat die waargenome en verwagte genotipefrekwensies vergelykbaar was vir gene SLC22A1, SLC22A4 en SLCO1A2, maar ons waargenome genotipefrekwensies was verskillend van die verwagte genotipefrekwensies vir die volgende gene SLCO1A2, CYP3A4 en CYP3A5. Interessante bevindings sluit in, die rs35191146 (ATG>AT: delG) wat swak Imatinibbehandelingsuitkoms gekoppel het, maar die gelyktydige teenwoordigheid van rs628031 (A>G: M408V) het hierdie effek omseil. Alle pasiente binne ons kohort het beide Met420 en Met408Val. Nog 'n interessante bevinding is die toevallige bevinding van variante SLC22A4 rs11568500 (c.616_617delinsCC), en SLC22A1 rs35191146 (c.1258_1260delATG en g.160139876_160139883delGTAAGTTG), wat verdeer ondersoek sal word in die toekoms. Selfs al beinvloed die geselekteerde SNV'e nie Imatinib-weerstandigheid in ons kohort nie, is ons studie na die beste van ons kennis die enigste studie om basislyn-alleliese en genotipiese frekwensies te bepaal vir CML-pasiente wat met Imatinib in Suid-Afrika behandel is. Daarom kan die data verkry uit ons studie dien as 'n nuttige hulpmiddel om die farmakogenetiese veranderlikheid in Suid-Afrika verder te ondersoek. Ten slotte, ons studie dra by tot die hoeveelheid kennis wat daar buite verband hou met SNV en die potensiele kliniese relevansie wat verband hou met imatinib-weerstand, veral binne ons diverse Afrika-kohort. Dit beklemtoon weer die behoefte aan toekomstige studies wat op groter kohorte fokus, met 'n groter keuse van SNV's by meer gesondheidsorginstellings regoor Suid-Afrikaaf_ZA
dc.description.versionMasters
dc.format.extentxiii, 113 pages : illustrations, includes annexures
dc.identifier.urihttp://hdl.handle.net/10019.1/127295
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch University
dc.rights.holderStellenbosch University
dc.subject.lcshChronic myeloid leukemia -- Treatment -- South Africaen_ZA
dc.subject.lcshDrug resistance -- South Africaen_ZA
dc.subject.lcshCancer -- Treatment -- South Africaen_ZA
dc.subject.nameUCTD
dc.titleImatinib resistance : the role of pharmacogenetic variability in a South African chronic myeloid leukemia cohorten_ZA
dc.typeThesisen_ZA
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