Genetic Variation - Effect on the Risk of Cancers of Lung and Oropharynx Genetic Variation - Effect on the Risk of Cancers of Lung and Oropharynx

............................................................................ 5 LIST OF ORIGINAL PUBLICATIONS ............................................... 6 ABBREVIATIONS ....................................................................... 7 INTRODUCTION ........................................................................ 8 REVIEW OF THE LITERATURE ...................................................... 10 Tobacco-induced cancers ......................................................... 10 Lung cancer .................................................................... 11 Oral and pharyngeal cancers .............................................. 13 Components of tobacco smoke ................................................. 14 Polyaromatic hydrocarbons ................................................ 15 N-Nitrosamines ................................................................ 16 Other compounds ............................................................. 17 Biological responses to tobacco smoke ...................................... 18 Biotransformation ............................................................ 18 Chemical carcinogenesis ................................................... 19 Genetic variation .................................................................... 23 Genetic susceptibility to cancer .......................................... 24 Glutathione-S-transferases ...................................................... 25 Substrates ...................................................................... 27 Expression ...................................................................... 27 GSTM1 and GSTM3 in cancer proneness .............................. 28 GSTP1 in cancer proneness ............................................... 31 GSTT1 in cancer proneness ............................................... 33 Microsomal epoxide hydrolase .................................................. 37 Substrates ...................................................................... 37 Expression ...................................................................... 38 EPHX1 in cancer proneness ............................................... 38 Validity of association studies ................................................... 40 Future trends ......................................................................... 41 Ethical aspects ....................................................................... 44 AIMS OF THE PRESENT STUDY .................................................... 46 MATERIALS AND METHODS ......................................................... 47 Study populations ...................................................................... 47 Finnish study populations .................................................. 47 French oral and pharyngeal cancer study population ............. 48 Methods ................................................................................ 49 Genotyping analysis ......................................................... 49 Sequencing ..................................................................... 50 Statistical analysis ............................................................ 50 RESULTS .................................................................................. 52 Characteristics of the study populations ..................................... 52 Finnish study populations ........................................................ 52 French oral and pharyngeal cancer study population ............. 52 GSTs and cancer proneness ..................................................... 53 Distribution of GSTM1, GSTP1 and GSTT1 genotypes in the population controls ........................................................... 53 GST genotypes and lung cancer risk ................................... 55 GST genotypes and oral and pharyngeal cancer risk .............. 55 EPHX1 and cancer proneness ................................................... 57 EPHX1 genotyping methodology ......................................... 57 Distribution of EPHX1 genotypes in the population controls .... 58 The EPHX1 genotypes and lung cancer risk .......................... 58 Combined effect of GSTs and EPHX1 on lung cancer proneness ..... 59 DISCUSSION ............................................................................ 61 GSTs .................................................................................... 61 General .......................................................................... 61 GSTM1 ........................................................................... 61 GSTM3 ........................................................................... 62 GSTP1 ............................................................................ 63 GSTT1 ............................................................................ 64 EPHX1 .................................................................................. 64 Focusing on pathways ............................................................. 66 Validity ................................................................................. 67 Future directions .................................................................... 69 CONCLUSIONS .......................................................................... 71 ACKNOWLEDGEMENTS ............................................................... 72 REFERENCES ............................................................................ 74 ORIGINAL PUBLICATIONS ........................................................... 99