Windsor, R; (2013) A pilot pharmacogenomics study examining the influence of cytotoxic and metabolising genetic polymorphisms on chemotherapy toxicity and outcome in osteosarcoma. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Background: Osteosarcoma is the most common malignant bone tumour in children and young people. Multi-agent MAP chemotherapy (Methotrexate, Adriamycin, cisPlatin) forms the backbone of standard treatment protocols but approximately 40% patients respond poorly to chemotherapy. It was hypothesized that pharmacogenomic profiling of osteosarcoma patients may facilitate optimisation of treatment with the aim of improved outcomes and decreased burden of late effects. This pilot study aimed to investigate associations of 36 candidate genetic polymorphisms in MAP pathway genes with histological response (HR), survival and grade 3-4 chemotherapy toxicity. A secondary aim was preliminary analysis of genome-wide copy number variation in osteosarcoma. Methods: Blood samples and retrospective chemotherapy toxicity data were obtained from 60 patients who had completed MAP chemotherapy. All patients were manually genotyped for 5 polymorphisms. The remaining 31 polymorphisms were genotyped in 50 patients using the Illumina 610-Quad microarray. Associations between candidate polymorphisms and HR, progression-free survival and toxicity were estimated using Pearson’s 2 and Fisher’s Exact tests, the Kaplan-Meier method, the log-rank test and Cox proportional hazards model. Copy number analysis was performed using PennCNV. Results: Poor histological response was associated with ABCC2 c.24C>T (p=0.011) and GSTP1 c.313A>G p.Ile105Val (p=0.009) whereas MTHFD1 c.1958G>A p.Arg653Gln was protective (p=0.03). Methotrexate toxicity was associated with MTHFR c.1298A>C p.Glu429Ala (p=0.038), ABCC2 c.3563T>A p.Val1188Glu (p=0.028) and ABCB1 c.3435T>C Ile145Ile (p=0.027). Variants of GSTP1 c.313A>G p.Ile105Val were at increased risk of myelosuppression (p=0.024) and cardiac damage (p=0.008). Eight recurrent copy number variations were identified, none significant. Conclusions: This pilot study explored the pharmacogenomics of osteosarcoma chemotherapy and although limited by small sample size secondary to retrospective recruitment and the rarity of this tumour, it remains the most comprehensive study to date. A number of novel polymorphic associations were observed as well as confirming several previously reported findings. Cautious interpretation is required but further prospective investigation is warranted.

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