LIFE09200604007 Tabish - Homi Bhabha National Institute

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Acknowledgments A sincere and heart filled gratitude to my supervisor Dr. Rita Mulherkar for giving me an opportunity to join her research group and making me realise the importance of studying genotype and phenotype correlation in understanding multiple primary cancers of upper-aero digestive tract. Her constant support, encouragement and guidance kept me sparked throughout my Ph.D tenure. I thank Dr. Rajiv Sarin (Director, ACTREC) and Dr. Surekha Zingde (Dy. Director ACTREC) for providing an excellent research infrastructure and CSIR govt. of India for the fellowship. I am thankful to all my doctoral committee members, Dr. R. Sarin (ACTREC), Dr. R. Mukhopadhyaya (ACTREC), Dr. M. Seshadri (BARC) and Dr. S. Galande (IISER), for their careful and timely revision and valuable comments for improving this project. I am thankful to staff in radiotherapy, CIR, imaging facility, flow-cytometry, photography, library and administration for their constant help and support. I am highly grateful to Ms. S. Kannan for helping with statistical analysis of the data and Dr. P. Kowtal, Ms. Payal and Ms. N. Bhatnagar for helping in sample collection form CGC, TMH. I want to express my warmest thanks to all Mulherkar lab members Dr. Ujjwala, Ashwin, Aditya, Vishal, Deepika, Asha and Poulami for all the support during these years and keeping the lab environment lively. Without excellent technical help, I could not have completed this study and I cannot forget to thank Ganeshji, Jadhavji and Raneji for their timely help. I would also like to thank all my trainees Gaurav, Ayushi, Dhanashree, Abhishek and Rashmi. I am also thankful to all my colleagues Amit S, Poulami, Manoj, Ajit, Amit R, Amit F, Sapana, Pallavi, Lalit, Atul and Amit V who kept the tough and tense days of my Ph.D as fun filled and joyous as possible. I am extremely thankful to one of my oldest friends from AMU, <strong>Tabish</strong> Rehman for being my supporting pillar. Finally, I dedicate my warmest thanks to all my family members Paapa, Mummy and my sisters for their love and endless support. Thank you all <strong>Tabish</strong> vi
CONTENTS Page No Synopsis 1 List of abbreviations 20 List of figures 22 List of tables 24 Chapter 1: INTRODUCTION 1.1 Introduction 25 1.2 Rationale of the study 26 1.3 Aim and objectives 28 Chapter 2: REVIEW OF LITERATURE 2.1 Upper aero-digestive tract cancer 29 2.2 Multiple primary Neoplasms 30 2.3 Understanding the pathogenesis of UADT MPN 32 2.4 Gene environment interaction 33 2.5 Single nucleotide polymorphism and genetic susceptibility 34 to UADT MPN 2.6 Genotype phenotype correlation studies 35 2.7 Model system: Epstein Barr virus transformed 35 lymphoblastoid cell lines 2.8 Molecular/intermediate phenotype associated with cancer risk 41 2.9 Gene polymorphisms associated with cancer risk 44 Chapter 3: MATERIALS AND METHODS 3.1 Accrual of UADT MPN patients and healthy matched controls 53 3.2 Generation of viable EBV stock 53 3.3 Lymphoblastoid cell line preparation 54 3.4 Characterization of LCL 55 3.5 Measurement of DNA damage and repair 63 3.6 Effect of genotoxic exposure on cell cycle profile 65 3.7 Measurement of percent cell death after genotoxic exposure 66 3.8 Genotyping of genes 67 3.9 Effect of γ-radiation on gene expression profiling 79 vii
Page 1: Genotype-Molecular Phenotype Correl
Page 9 and 10: Synopsis
Page 11 and 12: Synopsis Genotype-Molecular Phenoty
Page 13 and 14: Synopsis Materials and Methods: 1.
Page 15 and 16: Synopsis loading control. PCR produ
Page 17 and 18: Synopsis 7.1 Percent cell death aft
Page 19 and 20: Synopsis slides were then dried and
Page 21 and 22: Synopsis range 41.77% - 90.95% at 5
Page 23 and 24: Synopsis 5. Genotyping of genes: Ge
Page 25 and 26: Synopsis G2/M arrest and delaying e
Page 27 and 28: Synopsis may have an important bear
Page 29 and 30: Synopsis References: 1. Bobba, R.;
Page 31 and 32: Abbreviations MOPS : 3-(N-morpholin
Page 33 and 34: List of Figures Fig. 28: Percent re
Page 35 and 36: Chapter 1 Introduction
Page 37 and 38: Introduction In previous studies fr
Page 39 and 40: Introduction important carcinogenes
Page 41 and 42: Review of Literature The yet undeci
Page 43 and 44: Review of Literature Fig. 2: Incide
Page 45 and 46: Review of Literature sustained angi
Page 47 and 48: Review of Literature 2.6 Genotype p
Page 49 and 50: Review of Literature 2.7.2 Biologic
Page 51 and 52: Review of Literature Table 1: Steps
Page 53 and 54:
Review of Literature future analysi
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Review of Literature Inefficient ce
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Review of Literature XRCC1 (X-ray r
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Review of Literature 2.9.2 Gene inv
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Review of Literature MPO gene polym
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Review of Literature important role
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Materials and Methods Source of che
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Materials and Methods Method: EBV-t
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Materials and Methods Immunophenoty
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Materials and Methods with 500 μl
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Materials and Methods cDNA it can b
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Materials and Methods Cobalt-60 iso
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Materials and Methods specific bind
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Materials and Methods h half of the
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Materials and Methods phenol and th
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Materials and Methods 7. Filter ste
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Materials and Methods viz. EXO-SAP
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Materials and Methods Table 2: List
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Materials and Methods SMAD6 AREG HM
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Materials and Methods 3.9 Effect of
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Materials and Methods fresh eppendo
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Materials and Methods Power SYBR Gr
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Results Objective 1 To generate EBV
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Results Fig. 8: Frequency of second
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Results Table 6: Demographics of he
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Results Fig. 10: Cell population do
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Results Fig. 12: Cell surface marke
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Results 4.1.5 Expression of ATM gen
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Results Objective 2 To compare the
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Results Fig. 17: Standardization of
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Results Fig. 19: Standardisation of
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Results The cells were incubated fu
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Results 4.2.3.1 Percent G2 delay af
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Results 4.2.3.2 Effect of BPDE expo
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Results Fig. 29: Comparison of perc
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Results Fig. 31: Percent cell death
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Results normalization with baseline
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Results 4.2.5.2 Real time PCR valid
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Results homozygous wild-type, heter
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Results Fig. 36b: Electrophoresis o
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Results Fig. 37a: Representative el
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Results Table 13: Consolidated geno
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Results LCL Genes NAT2(1) NAT2(2) N
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Results Fig. 38: Distribution of Ge
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Results Fig. 39: Various combinatio
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Results Table 14: Genotype-phenotyp
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Discussion Introduction Squamous ce
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Discussion stimulated lymphocytes w
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Discussion H2AX is currently the mo
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Discussion or G2/M phase arrest. As
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Discussion differential expression
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Discussion DNA repair genes and MPN
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Chapter 6 Summary and Conclusions
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Summary and Conclusions Statistical
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Bibliography 1. Dikshit, R.; Gupta,
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Bibliography 43. Lei, D.; Sturgis,
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Bibliography 76. Fry, R. C.; Svenss
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Bibliography 115. Kote-Jarai, Z.; M
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Bibliography 149. Hashibe, M.; Bren
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Bibliography 183. Bergamaschi, D.;
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Bibliography 216. Bondy, M. L.; Wan
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Indian J Med Res 135, June 2012, pp
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822 INDIAN J MED RES, JUNE 2012 mar
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824 INDIAN J MED RES, JUNE 2012 (h)
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826 INDIAN J MED RES, JUNE 2012 Tab
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828 INDIAN J MED RES, JUNE 2012 lik
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CASE REPORT Eben L. Rosenthal, MD,
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FIGURE 2. Chromosomal breakage anal
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FA along with ataxia telangiectasia
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LIFE09200604007 Tabish - Homi Bhabha National Institute

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