LIFE09200604007 Tabish - Homi Bhabha National Institute

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Review of Literature exposures including environmental factors could contribute to the development of UADT MPN. 2.5 Single nucleotide polymorphism and genetic susceptibility to UADT MPN Presently much emphasis has been laid on understanding effect of gene polymorphisms in terms of their associations with risk of various cancers. The genetic component influencing susceptibility to cancer includes gene falling mainly in important carcinogenesis pathways of DNA repair, carcinogen metabolism, cell cycle regulation and cell death control. Variation in any of these mechanisms may result in accumulation of cell with genetic alteration in critical genes leading to tumourigenesis 9 . So far no single gene mutation/ variation has been attributed to be the cause of UADT MPN. Hence cumulative effects of low penetrance genes are likely to contribute susceptibility to such cancers. Evidences from various studies analyzing cumulative polymorphisms suggest aberrant gene-environment interactions to be an important etiological factor in carcinogenesis. A large number of case control studies have attempted to establish the role of polymorphisms in critical regulatory pathway genes with susceptibility to development of second primary tumours 7, 12, 40-44 . Studies from our own group describe the involvement of single nucleotide polymorphisms and genetic susceptibility in etiology of UADT MPN in Indian population. In studies done by Jhavar et al., GSTM1 and GSTT1 gene null genotype has been found to confer risk for developing UADT MPN in Indian males using tobacco and females with paired occurrence of cancers in UADT and genital region 7, 45 . In another case-control study and meta-analysis of SULT1A1 Arg 213 His polymorphism from our group, UADT MPN patients showed significant risk association with SULT1A1 gene polymorphism 12 . As risk assessment for cancer risk is moving toward a multigenic pathway-based approach in a recent report from our lab in an attempt to understand collective effect of a panel of SNPs, an association of polymorphisms in genes falling in major carcinogenesis pathways was observed in MPN patients with tobacco habit 40 . These studies emphasise the role of genetic predisposition in UADT MPN and importance of undertaking studies evaluating a cumulative effect of panel of important gene SNPs. 34
Review of Literature 2.6 Genotype phenotype correlation studies Since last few decades a number of studies have reported association of gene polymorphisms with cancer risk. However the real implication of these gene polymorphisms with increased cancer risk can only be interpreted if they have any functional significance. Therefore undertaking genotype-phenotype correlation studies is extremely important to understand the functional significance of the gene polymorphisms. Numerous studies have been conducted during last one decade to evaluate the functional significance of gene polymorphisms in normal individuals 46-48 . This approach of understanding effect of gene polymorphisms at functional level has been phenomenal and has been applied to deduce the functional significance of genetic predisposition in cancer risk 49-52 . One of such reports describes alteration in the apoptotic capacity to be a risk factor for lung cancer development and the risk was observed to be modulated by the Fas -A 670 G polymorphism 51 . Similarly, variations in p53 gene have been associated with apoptosis and DNA repair and in turn with lung cancer risk 53 . On the contrary XPA gene polymorphism, a DNA binding protein in the nucleotide excision repair pathway, has been observed to modulate repair capacity and is associated with decreased lung cancer risk, especially in the presence of exposure to tobacco carcinogens 52 . Other than lung cancer, analogous reports are available for breast cancer also where polymorphisms in nucleotide excision repair genes and DNA repair capacity phenotype has been with breast cancer risk 54, 55 . In another report by Minard et al. evaluation of glutathione S-transferase polymorphisms and mutagen sensitivity as risk factors for the development of second primary tumours in 303 patients previously diagnosed with early-stage head and neck cancer has been done 49 . These studies demonstrate the functional significance of genetic variation in different individuals and then their probable implication on various phenotypes and eventually cancer risk, hence emphasizing the importance of undertaking genotype-phenotype correlation studies in understanding UADT MPN pathogenesis. 2.7 Model system: Epstein Barr virus transformed lymphoblastoid cell lines In order to understand the etiology of UADT MPN there is a need to undertake genotype phenotype correlation studies. However, one of the prime requisites for performing long term genotype-phenotype correlation studies is the continuous supply of starting parent material. This can be overcome to some extent by establishing 35
Page 1: 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: Review of Literature sustained angi
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 and 58: Review of Literature XRCC1 (X-ray r
Page 59 and 60: Review of Literature 2.9.2 Gene inv
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
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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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