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A Pilot Pharmacogenomic Study Examining the Influence of Cytotoxic and Metabolising Genetic Polymorphisms on Chemotherapy Toxicity and Outcome in Osteosarcoma

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A Pilot Pharmacogenomic Study Examining the Influence of Cytotoxic and Metabolising Genetic Polymorphisms on Chemotherapy Toxicity and Outcome in Osteosarcoma A PILOT PHARMACOGENOMIC STUDY EXAMINING THE INFLUENCE OF CYTOTOXIC AND METABOLISING GENETIC POLYMORPHISMS ON CHEMOTHERAPY TOXICITY AND OUTCOME IN OSTEOSARCOMA DR RACHAEL WINDSOR BSc, MBBS, MRCPCH, MSc UNIVERSITY COLLEGE LONDON FACULTY OF CLINICAL SCIENCES MD(Res) CLINICAL RESEARCH January 2013 MD Res Pharmacogenomics of Osteosarcoma January 2013 1 DECLARATION ‘I, Rachael Windsor confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' MD Res Pharmacogenomics of Osteosarcoma January 2013 2 ABSTRACT Background: Osteosarcoma is the most common malignant bone tumour in children and young people. Multi-agent MAP chemotherapy ( Methotrexate, Adriamycin, cis Platin) 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 χ2 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.Ile 105 Val (p=0.009) whereas MTHFD1 c.1958G>A p.Arg 653 Gln was protective (p=0.03). Methotrexate toxicity was associated with MTHFR c.1298A>C p.Glu 429 Ala (p=0.038), ABCC2 c.3563T>A p.Val 1188 Glu (p=0.028) and ABCB1 c.3435T>C Ile 145 Ile (p=0.027). Variants of GSTP1 c.313A>G p.Ile 105 Val 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 MD Res Pharmacogenomics of Osteosarcoma January 2013 3 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. MD Res Pharmacogenomics of Osteosarcoma January 2013 4 Table of Contents List of abbreviations............................................................................................8 1.0 Introduction .................................................................................................10 1.1 Candidate polymorphism study ...............................................................10 1.2 Genome wide analysis of CNV................................................................12 2.0 Osteosarcoma: background........................................................................13 2.1 Clinical and pathological features............................................................13 2.2 Current therapeutic strategy....................................................................14 Figure 1: MAP chemotherapy schematic ...................................................16 2.3 Osteosarcoma: late effects of chemotherapy ..........................................17 2.3.1 Cardiotoxicity ....................................................................................17 Figure 2: The relationship between cardiac and non-cardiac findings in long-term survivors of childhood malignancy treated with anthracyclines..18 Figure 3: Candidate genes involved in adverse effects of doxorubicin in a cardiomyocyte............................................................................................19 2.3.2 Nephrotoxicity ...................................................................................20 2.3.3 Ototoxicity .........................................................................................20 2.3.4 Fertility ..............................................................................................21 3.0 Pharmacology and pharmacogenomics of MAP chemotherapy..................23 3.1 Pharmacology of MAP chemotherapy .....................................................23 3.1.1 Methotrexate.....................................................................................23 Figure 4: Methotrexate drug pathway ........................................................25 3.1.2 Doxorubicin.......................................................................................26 Figure 5: Doxorubicin drug pathway ..........................................................28 3.1.3 Cisplatin............................................................................................29 Figure 6: Platinum drug pathway ...............................................................31 3.2 Pharmacogenomics of MAP chemotherapy ............................................32 Table 1: Functional and clinical effects of candidate polymorphisms.........33 3.2.1 The folate pathway (MTX).................................................................38 3.2.2 ATP-Binding Cassette Transporters (MTX, DOX, cisplatin)..............40 3.2.3 Glutathione S-transferases (cisplatin, DOX) .....................................42 3.2.4 Nucleotide excision repair (cisplatin, DOX).......................................44 3.2.5 Carbonyl reductases, NAD(P)H oxidase (DOX)................................46 4.0 Copy number variation................................................................................48 4.1 CNV in osteosarcoma .............................................................................49 Figure 7: Proposed model for CNVs in tumourigenesis .............................50 5.0 Materials and Methods (i): Candidate polymorphism study ........................53 5.1 Study population......................................................................................53 5.1.1 Patient identification..........................................................................53 5.1.2 Ethics................................................................................................53 5.2 Data collection.........................................................................................53 5.2.1 Demographic data ............................................................................53 5.2.2 Chemotherapy toxicity ......................................................................54 Table 2: CTCAE grades for cardiac, renal and ototoxicity .........................55 5.3 Selection of candidate polymorphisms ....................................................56 5.4 Preparation of DNA .................................................................................56 5.4.1 Extraction of genomic DNA from whole blood...................................56 5.4.2 Quantification....................................................................................56 5.5 SNP microarray analysis .........................................................................56 5.5.1 Illumina 610-Quad SNP array ...........................................................57 Figure 8: Illumina 610-Quad microarray ....................................................57 MD Res Pharmacogenomics of Osteosarcoma January 2013 5 5.5.2 Infinium HD whole-genome genotyping single base extension assay (WGG-SBE)...............................................................................................57 Figure 9: Infinium HD WGG-SBE assay ....................................................58 5.6 Polymerase chain reaction (PCR) ...........................................................59 5.6.1 Standard PCR...................................................................................59 5.6.1.1 TS VNTR final amplification ...........................................................60 5.6.1.2 DHFR in/del ...................................................................................60 Table 3: PCR Primer sequences and fragment size ..................................60 Table 4: TS VNTR optimisation steps........................................................61 5.6.1.3 RFLP analysis: TS VNTR G/C SNP...............................................61 Figure 10: Hae III restriction sites ..............................................................62 5.7 Multiplex PCR: GSTT1 and GSTM1 null alleles ......................................62 5.7.1 Gel electrophoresis...........................................................................62 Image 1: TS VNTR gel electrophoresis .....................................................63 Image 2: TS Triple repeat G/C SNP ..........................................................63 Image 3: DHFR electrophoresis.................................................................63 Image 4: GSTT1/GSTM1 electrophoresis..................................................64
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