LIFE09200604007 Tabish - Homi Bhabha National Institute

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Review of Literature Fig. 3: Sagittal section of Upper aero digestive tract showing various cancer sites in humans. (Tobias, 1994) 2.3 Understanding the pathogenesis of UADT MPN Various theories have been put forward to understand etiology of UADT MPN, the earliest being the concept of „Field cancerization‟ described by Slaughter and Southwick in 1953. They demonstrated that second primary tumours develop independently from the first primary tumour because of the widespread exposure to carcinogens in the upper aero-digestive tract mucosa. They found that total epithelium beyond the boundaries of the tumour showed histological changes, suggesting that due to carcinogen exposure mucosa of the head and neck undergoes a change and becomes more susceptible to the development of many foci of malignant transformation 29 . Later Braakhuis et al. provided a genetic explanation of field cancerization and described a „progression model‟ according to which a cell acquires one (or more) genetic alterations and forms a patch with genetically altered daughter cells. This genetically altered patch expands into a field of epithelial lesion with cancer related genetic alterations and later develops into multiple primary tumours 30 . It is now well established that cancers develop through a multistep process of genetic alterations mainly to oncogenes and tumour-suppressor genes. These genetic alterations disrupt several molecular pathways and the cell acquire sustained proliferative signalling, insensitivity to growth repressors, resistance to cell death, replicative immortality, 32
Review of Literature sustained angiogenesis, invasion, metastasis, reprogrammed energy metabolism and immune evasion 31 . Therefore UADT MPN may also arise due to genetic susceptibility. The reason for acquisition of genetic alterations in head and neck cancers can be mainly attributed to carcinogenic exposure. Tobacco and alcohol are considered to be the major risk determinant for these cancers 15, 32 . Exposure to tobacco alone or in combination with heavy alcohol consumption can disrupt genomic integrity which contributes to malignant transformation and subsequent cancer development 15, 33, 34 . Since only a fraction of exposed individuals develop the disease therefore an intrinsic susceptibility to environmental genotoxic exposures has also been suggested as playing an important role. Consequently there is a possibility of a different host environment interaction in individuals who develop such MPN. 2.4 Gene environment interaction Cancer is a multi-factorial disease that arises due to aberrations in many cellular functions that are involved in the normal cellular homeostasis 31 . Although, the exact origin or cause of UADT MPN is still not well understood, but it appears to develop in a susceptible host where both genetic and environmental factors play a significant role in initiation of such sporadic cancers 35 . The involvement of environmental factors in cancer predisposition is known since 18 th century when Percival Pott identified soot as a possible agent causing scrotal cancer in chimney sweepers 36 . Since then it has been established that environmental factors play an important role in the etiology of sporadic human cancers 37 . However it is well accepted that all individuals exposed to same type and dose of carcinogens do not develop cancer and there is a considerable inter-individual variations that influences the way an individual handles the genotoxic insult and thus susceptibility to cancer. This difference could arise due to varied interaction of the carcinogens with genes that are involved in carcinogen detoxification, repair of damaged DNA, cell cycle and cell death regulation. The variation in gene-carcinogen interaction can be a consequence of cumulative effect of mutations and polymorphisms in these genes that fall in important carcinogenesis pathways. Each variant allele confers a small genotyping risk that combines additively or multiplicatively to confer range of cancer susceptibilities 7, 12, 38-40 . Therefore genetic predisposition alone may not be responsible for causing cancer but a combination of susceptibility genes and 33
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: Review of Literature Fig. 2: Incide
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 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
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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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