Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients

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dc.contributor.advisorRamesar, Rajkumaren_ZA
dc.contributor.advisorVorster, Anna Alveraen_ZA
dc.contributor.authorSpracklen, Timothy Francisen_ZA
dc.date.accessioned2016-07-20T12:34:12Z
dc.date.available2016-07-20T12:34:12Z
dc.date.issued2016en_ZA
dc.description.abstractCisplatin, a potent chemotherapeutic agent, is widely used in the treatment of numerous soft-tissue cancers. Although high cure rates can be achieved when cisplatin is incorporated in chemotherapy regimens, the therapeutic utility of the drug may be limited by the development of dose-limiting adverse reactions in patients. A prevalent reaction to cisplatin is ototoxicity, or drug-induced hearing loss, which occurs when the drug accumulates in and damages cells of the inner ear, leading to permanent and progressive hearing impairment. In this investigation, two approaches were employed to explore the role of genetics in cisplatin response amongst South African cancer patients (n = 214). Using a candidate gene approach, which investigated variants in six genes which are involved in drug transport and processing, potential modifiers in the genes nuclear factor, erythroid 2-like 2 (NFE2L2) and solute carrier family 22, member 2 (SLC22A2) were identified. SLC22A2 encodes a known transporter of cisplatin, and the variant rs316019 conferred potentially protective effects against Chang- and TUNE-graded ototoxicity through a reduced transport of the drug (p = 0.039 and p = 0.031, respectively). Similarly, the variant NFE2L2 rs6721961 was possibly protective, as it occurred more frequently in patients who did not develop hearing impairment according to four different ototoxicity grading scales during high-dose (≥ 200 mg/m2) cisplatin treatment (ASHA, p = 0.001; Chang, p = 0.022; CTCAE, p = 0.001; TUNE, p = 0.028). When supplementing the prospective cohort with retrospective patient data, an increased susceptibility of indigenous African patients to Chang grade > 0 ototoxicity was observed (p = 0.001). For this reason, whole-exome sequencing was conducted on a subset of the patient cohort (n = 11), focussing on individuals of African origin who represented the phenotype extremes. Potential genetic modifiers were identified in genes involved in various biological processes, including transmembrane transport, development, hearing, the response to DNA damage, immune reactions and signalling pathways, implicating many previously unreported genes in the cellular response to cisplatin as well as its ototoxicity. The results reported in this study indicate that genetic information can improve predictive models of cisplatin response, although there are many novel genes which should be explored in the South African population. Identifying these genetic modifiers, such as those in SLC22A2 and NFE2L2, has the potential to further our understanding of this adverse drug reaction, and may assist in the future personalisation of treatment plans in the management of cancer.en_ZA
dc.identifier.apacitationSpracklen, T. F. (2016). <i>Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics. Retrieved from http://hdl.handle.net/11427/20540en_ZA
dc.identifier.chicagocitationSpracklen, Timothy Francis. <i>"Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2016. http://hdl.handle.net/11427/20540en_ZA
dc.identifier.citationSpracklen, T. 2016. Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Spracklen, Timothy Francis AB - Cisplatin, a potent chemotherapeutic agent, is widely used in the treatment of numerous soft-tissue cancers. Although high cure rates can be achieved when cisplatin is incorporated in chemotherapy regimens, the therapeutic utility of the drug may be limited by the development of dose-limiting adverse reactions in patients. A prevalent reaction to cisplatin is ototoxicity, or drug-induced hearing loss, which occurs when the drug accumulates in and damages cells of the inner ear, leading to permanent and progressive hearing impairment. In this investigation, two approaches were employed to explore the role of genetics in cisplatin response amongst South African cancer patients (n = 214). Using a candidate gene approach, which investigated variants in six genes which are involved in drug transport and processing, potential modifiers in the genes nuclear factor, erythroid 2-like 2 (NFE2L2) and solute carrier family 22, member 2 (SLC22A2) were identified. SLC22A2 encodes a known transporter of cisplatin, and the variant rs316019 conferred potentially protective effects against Chang- and TUNE-graded ototoxicity through a reduced transport of the drug (p = 0.039 and p = 0.031, respectively). Similarly, the variant NFE2L2 rs6721961 was possibly protective, as it occurred more frequently in patients who did not develop hearing impairment according to four different ototoxicity grading scales during high-dose (≥ 200 mg/m2) cisplatin treatment (ASHA, p = 0.001; Chang, p = 0.022; CTCAE, p = 0.001; TUNE, p = 0.028). When supplementing the prospective cohort with retrospective patient data, an increased susceptibility of indigenous African patients to Chang grade > 0 ototoxicity was observed (p = 0.001). For this reason, whole-exome sequencing was conducted on a subset of the patient cohort (n = 11), focussing on individuals of African origin who represented the phenotype extremes. Potential genetic modifiers were identified in genes involved in various biological processes, including transmembrane transport, development, hearing, the response to DNA damage, immune reactions and signalling pathways, implicating many previously unreported genes in the cellular response to cisplatin as well as its ototoxicity. The results reported in this study indicate that genetic information can improve predictive models of cisplatin response, although there are many novel genes which should be explored in the South African population. Identifying these genetic modifiers, such as those in SLC22A2 and NFE2L2, has the potential to further our understanding of this adverse drug reaction, and may assist in the future personalisation of treatment plans in the management of cancer. DA - 2016 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2016 T1 - Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients TI - Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients UR - http://hdl.handle.net/11427/20540 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/20540
dc.identifier.vancouvercitationSpracklen TF. Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2016 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/20540en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Human Geneticsen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherPathologyen_ZA
dc.titleInvestigating the genetic basis of cisplatin-induced ototoxicity in adult South African patientsen_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMSc (Med)en_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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