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Title: An investigation of the pharmacogenetic basis of toxicity to platinum chemotherapy agents
Author: Corrigan, Adele
ISNI:       0000 0004 5988 9924
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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Background: Platinum-based chemotherapy is the main stay of first line treatment for a number of tumour types. However, toxicity is a significant issue, particularly haematological toxicity and sepsis leading to morbidity, hospital admissions and delay or loss in optimal chemotherapy regimens. Few studies have addressed the pharmacogenetic influence in platinum toxicity outcomes; the likelihood of genetic influence is high. Identification of those at greatest risk using robust predictive pharmacogenetic markers may aid clinical decision making and minimise risk to the patient. Methods: Illumina Human Exome BeadChip technology was used to genotype >240,000 single nucleotide variants from across the exome. An unbiased exome-wide analysis was carried out to identify variants associated with the most pertinent toxicity outcomes within cisplatin and carboplatin treated discovery (n=381) and replication (n=221) cohorts, as well as an independent oxaliplatin treated cohort (n=359). Subsequently, an extensive candidate gene analysis of common toxicity outcomes was undertaken to verify previously reported toxicity markers and explore previously unstudied genes in well-powered cohorts. Results: Exome-wide analyses identified a number of promising, novel associations, including those of C7orf57 rs2708890 and AQP8 rs111840156 with gastrointestinal toxicity and thrombocytopaenia respectively, which were validated across cohorts. Within the oxaliplatin treated cohort, variants within cancer susceptibility genes CASC8/CCAT2 were associated with gastrointestinal toxicity and a number of functionally plausible genes including SNAP47, POLR3 and ARGHEF10 were associated with peripheral neuropathy. Previously reported pharmacogenetic associations of XPC rs2228001, GSTP1 rs1695 and REV1 rs3087386 were validated in the candidate gene analysis of the discovery cohort. Similarly, ERCC2, ATR, GEN1 and EPHX1 variants were associated with oxaliplatin outcomes here, in agreement with the findings of previous studies. Conclusions: The research presented within this thesis represents an original contribution to the current understanding of the genetic component of platinum tolerability. The use of exome chip technology has enabled both an unbiased assessment of genetic variation from across the exome and an opportunity to independently replicate previous findings. This research offers key insights and will be a valuable resource for future studies in the field.
Supervisor: Sanderson, Jeremy ; Spicer, James Frederick Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available