LIFE09200604007 Tabish - Homi Bhabha National Institute

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Review of Literature genotoxic agents including tobacco carcinogens. Several XPD polymorphisms have been identified in the coding regions with a relatively high frequency 129 . The XPDexon23 Lys 751 Gln is one of the very well studied polymorphism and is implicated in Lung cancer and head and neck cancers 118, 130, 131 . In a study performed on Indian population presence of the polymorphic variant of XPD was associated with increased risk of oral cancer compared to the wild genotype 132 . In a recent meta analysis that comprised 15 published case-control studies examining the association of head and neck cancer risk with XPD Lys 751 Gln polymorphism in different populations a significantly elevated cancer risk was associated with the polymorphism and it was considered to be a prediction marker for risk of head and neck cancer 133 . hOGG1 (Human 8-oxoguanine DNA glycosylase) Gene encodes the enzyme responsible for the excision of 8-oxoguanine, a mutagenic base by product which occurs as a result of exposure to reactive oxygen by base excision repair. 8-oxoguanine adducts are produced during oxidative DNA damage by carcinogens including tobacco. A nonsynonymous hOGG1-exon7 Ser 326 Cys polymorphism has frequently been associated with head and neck cancer in various population based studies 134-136 . In a recent study done on 92 patients with primary HNSCC an association between the Cys/Cys 326 genotype and HNSCC with cigarette smoking was observed 134 . In another report Ser 326 Cys variant genotype was found to be associated with an increased risk of HNSCC in north Indian population and was claimed to serve as a biomarker for early diagnosis of HNSCC 135 . BRCA2 (Breast cancer 2) BRCA2 is a tumour suppressor gene and the protein encoded by this gene is involved in the repair of chromosomal damage with an important role in the error free repair of DNA double strand breaks. This gene is present in the region of chromosome 13 which has been implicated to harbour alterations in HNSCC 137, 138 . In present study we are undertaking two BRCA2 gene polymorphisms viz. BRCA2 -26 G/A 5'UTR polymorphism and BRCA2-exon10 Asn 372 His polymorphism. As this gene has an important role in DNA damage repair therefore polymorphisms in the gene may have an association with cancer risk. In our earlier study, increased risk association was observed for MPN patients with at least one tobacco related cancer in the upper aero digestive tract with BRCA2-exon10 Asn 372 His polymorphism 40 . 46
Review of Literature 2.9.2 Gene involved in detoxification of carcinogens The metabolism of carcinogens is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify carcinogens and remove them from system. The phase I enzymes activate the carcinogens by oxidation, reduction, hydrolysis and/or hydration. In subsequent phase II reactions, these activated carcinogen metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid. After phase II reactions the carcinogen conjugates can be excreted from cells in bile or urine. Together these enzymes are known as carcinogen metabolizing enzymes. Polymorphisms in genes encoding these enzymes can modify an individual‟s response to carcinogen exposure. The genes that are undertaken for genotyping in present study are described below: GSTM1 (Glutathione-S-Transferase-Mu 1) Glutathione-S-transferases are phase II detoxification enzymes that catalyses the conjugation of sulfhydryl group of glutathione (GSH) to a wide variety of carcinogens hence making them water soluble for excretion mainly through urine. GSTM1 is one of the enzymes of mu class 139 . Loss of GSTM1 enzyme function is due to homozygous deletion resulting in the GSTM1 null genotype 140 . GSTM1 null genotype is very well studied in terms of having an association with increased risk of head neck cancer in population based studies 141-143 . The risk conferred by GSTM1 null genotype was observed in Asians with head and neck cancer in meta analysis of 22 case control studies 144 . GSTM1 null genotype is also found to be a risk factor for developing multiple primary neoplasms in the upper aero-digestive tract in Indian males using tobacco 7 . In a similar study done on MPN patients, subjects with a single tumour of head and neck and cancer-free male volunteer, GSTM1 null polymorphism was found to be associated with MPN 10 . In few studies GSTM1 null genotype is shown to have an additive interaction with smoking on head and neck cancer risk 145 . GSTT1 (Glutathione-S-Transferase-Theta 1) The enzyme encoded by the gene is one of the members of theta class of GSTs. GSTT1 null genotype is found to be associated with risk for head and neck cancer 146 . More often GSTT1 polymorphism is evaluated with GSTM1 polymorphism and represents association with cancers of head and neck 141, 147, 148 . GSTT1 null genotype confers risk to males with MPN in the head and neck 7 . In the meta-analysis 47
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Genotype-Molecular Phenotype Correl
Page 7 and 8: CONTENTS Page No Synopsis 1 List of
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
Page 55 and 56: Review of Literature Inefficient ce
Page 57: Review of Literature XRCC1 (X-ray r
Page 61 and 62: Review of Literature MPO gene polym
Page 63 and 64: Review of Literature important role
Page 65 and 66: Materials and Methods Source of che
Page 67 and 68: Materials and Methods Method: EBV-t
Page 69 and 70: Materials and Methods Immunophenoty
Page 71 and 72: Materials and Methods with 500 μl
Page 73 and 74: Materials and Methods cDNA it can b
Page 75 and 76: Materials and Methods Cobalt-60 iso
Page 77 and 78: Materials and Methods specific bind
Page 79 and 80: Materials and Methods h half of the
Page 81 and 82: Materials and Methods phenol and th
Page 83 and 84: Materials and Methods 7. Filter ste
Page 85 and 86: Materials and Methods viz. EXO-SAP
Page 88 and 89: Materials and Methods Table 2: List
Page 90 and 91: Materials and Methods SMAD6 AREG HM
Page 92 and 93: Materials and Methods 3.9 Effect of
Page 94 and 95: Materials and Methods fresh eppendo
Page 96 and 97: Materials and Methods Power SYBR Gr
Page 98 and 99: Results Objective 1 To generate EBV
Page 100 and 101: Results Fig. 8: Frequency of second
Page 102 and 103: Results Table 6: Demographics of he
Page 104 and 105: Results Fig. 10: Cell population do
Page 106 and 107: 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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