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

 

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dc.contributor.advisor Ramesar, Rajkumar en_ZA
dc.contributor.advisor Vorster, Anna Alvera en_ZA
dc.contributor.author Spracklen, Timothy Francis en_ZA
dc.date.accessioned 2016-07-20T12:34:12Z
dc.date.available 2016-07-20T12:34:12Z
dc.date.issued 2016 en_ZA
dc.identifier.citation Spracklen, T. 2016. Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients. University of Cape Town. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/20540
dc.description.abstract 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. en_ZA
dc.language.iso eng en_ZA
dc.subject.other Pathology en_ZA
dc.title Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients en_ZA
dc.type Master Thesis
uct.type.publication Research en_ZA
uct.type.resource Thesis en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Division of Human Genetics en_ZA
dc.type.qualificationlevel Masters
dc.type.qualificationname MSc (Med) en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Spracklen, 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/11427/20540 en_ZA
dc.identifier.chicagocitation Spracklen, 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/11427/20540 en_ZA
dc.identifier.vancouvercitation Spracklen 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/11427/20540 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


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