Microarrays in Lung Cancer Research: From Comparative Analyses to Verified Findings
نویسندگان
چکیده
........................................................................................................................................ 5 LIST OF ORIGINAL PUBLICATIONS............................................................................................. 7 ABBREVIATIONS .............................................................................................................................. 8 REVIEW OF LITERATURE............................................................................................................ 10 1 CANCER GENETICS .................................................................................................................. 10 1.1 Oncogenes and tumor suppressor genes......................................................................... 10 1.2 Genetic instability ......................................................................................................... 12 1.3 Genomic alterations ...................................................................................................... 13 1.4 Fragile sites .................................................................................................................. 14 1.5 Signaling pathways ....................................................................................................... 15 2 LUNG CANCER ........................................................................................................................ 16 2.1 Histological classification of LC.................................................................................... 16 2.2 Risk factors for LC ........................................................................................................ 17 2.3 Genetic alterations in LC............................................................................................... 17 Changes in LC related to smoking............................................................................................... 18 Changes in LC related to asbestos............................................................................................... 19 3 MICROARRAYS IN CANCER RESEARCH ...................................................................................... 20 3.1 Microarray data processing .......................................................................................... 21 3.2 Pathway analysis of microarray data............................................................................. 22 Gene Ontology............................................................................................................................ 23 3.3 Combining array CGH and gene expression .................................................................. 24 3.4 Considerations related to microarray analyses .............................................................. 25 3.5 Microarrays in lung cancer ........................................................................................... 26 AIMS OF THE STUDY ..................................................................................................................... 28 MATERIALS..................................................................................................................................... 29 1 STUDY SUBJECTS..................................................................................................................... 29 1.1 Asbestos related studies (II-V) ....................................................................................... 29 1.2 Studies related to disseminating LCs (VI)....................................................................... 29 2 MICROARRAY ANALYSIS METHODS .......................................................................................... 31 2.1 Three-color image analysis (I)....................................................................................... 31 2.2 Array CGH (II, IV & VI)................................................................................................ 32 2.3 Gene expression microarrays (III, V & VI)..................................................................... 33 2.4 Differential region finding method (II, III & VI)............................................................. 34 2.5 ROC curves (III & VI) ................................................................................................... 35 2.6 GO analysis (V)............................................................................................................. 35 3 VERIFICATION METHODS ......................................................................................................... 36 3.1 Microsatellite analysis of 19p (III)................................................................................. 36 3.2 FISH (IV & VI).............................................................................................................. 37 3.3 Evaluation of UBA1 and UBA7 levels by Western blotting (V)........................................ 37 3.4 Studies on human bronchial epithelial BEAS 2B cells (IV) ............................................. 38 RESULTS........................................................................................................................................... 39 1 THREE-COLOR IMAGE ANALYSIS (I) ........................................................................................ 39 2 DIFFERENTIAL REGION FINDING (II, III & VI) ........................................................................... 39 3 ASBESTOS RELATED CHANGES ................................................................................................. 40 3.1 Molecular changes of asbestos related tumors (II & III)................................................. 40 3.2 Region 19p in asbestos related carcinogenesis (III & IV) ............................................... 41 19p aberrations revealed by array CGH (IV)............................................................................... 41 Microsatellite analysis (III)......................................................................................................... 42 FISH (IV).................................................................................................................................... 43 Micronuclei induced by crocidolite asbestos (IV)......................................................................... 44 3.3 Asbestos related deregulated pathways (V) .................................................................... 45 4 MOLECULAR CHANGES OF TUMORS WITH DTCS IN BM (VI) ........................................................ 46 DISCUSSION..................................................................................................................................... 48
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