Chapter 2 - University of British Columbia
Chapter 2 - University of British Columbia
Chapter 2 - University of British Columbia
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5.2 Genomic alterations ........................................................................................................ 113<br />
5.2.1 Chromosomal aberrations ........................................................................................ 113<br />
5.2.2 Gene dosage, allelic imbalance, mutational status ................................................... 113<br />
5.2.3 Genomic landscape: Gains, losses and uniparental disomy .................................... 116<br />
5.3 Epigenomic alterations .................................................................................................... 117<br />
5.3.1 The cancer methylome ............................................................................................. 117<br />
5.3.2 Integration <strong>of</strong> cancer genomic and epigenomic events ............................................ 119<br />
5.4 Relating genetic and epigenetic events to changes in the transcriptome through<br />
integrative analysis ................................................................................................................ 120<br />
5.4.1 Multiple mechanisms <strong>of</strong> gene disruption ................................................................... 121<br />
5.4.2 Multiple mechanisms <strong>of</strong> disrupting non-coding RNA levels ...................................... 121<br />
5.4.3 Multi-dimensional integration <strong>of</strong> genome, epigenome, and transcriptome ............... 122<br />
5.4.4 Disruption <strong>of</strong> multiple components in biological pathways ........................................ 124<br />
5.4.5 Identification <strong>of</strong> a novel gene involved with EGFR signaling deregulated in<br />
adenocarcinoma ................................................................................................................ 125<br />
5.4.6 Prevalence <strong>of</strong> SIRPA deregulation and association with clinical characteristics ...... 126<br />
5.5 Tracking clonal expansion in spatial dimensions ............................................................ 127<br />
5.6 Evaluating the biological significance <strong>of</strong> integrative genomics findings .......................... 127<br />
5.5 References ...................................................................................................................... 144<br />
<strong>Chapter</strong> 6: Conclusions ............................................................................................................. 162<br />
6.1 Summary ......................................................................................................................... 163<br />
6.1.1 Development <strong>of</strong> the integrative genetic and epigenetic approach ............................ 163<br />
6.1.2 Identification <strong>of</strong> a prevalent genetic alteration in lung adenocarcinoma ................... 164<br />
6.1.3 Application <strong>of</strong> the integrative approach to lung adenocarcinoma specimens ........... 165<br />
6.2 Conclusions ..................................................................................................................... 166<br />
6.3 Future directions .............................................................................................................. 168<br />
6.4 References ...................................................................................................................... 171<br />
APPENDIX I: List <strong>of</strong> publications .............................................................................................. 174<br />
APPENDIX II: Description <strong>of</strong> cell lines ...................................................................................... 183<br />
APPENDIX III: Sources <strong>of</strong> data ................................................................................................. 184<br />
APPENDIX IV: MCD strategy and Kaplan-Meier analysis <strong>of</strong> TUSC3 ....................................... 185<br />
APPENDIX V: Kaplan-Meier and Oncomine expression analysis <strong>of</strong> frequent MCD genes ...... 186<br />
APPENDIX VI: Summary <strong>of</strong> Kaplan-Meier survival analysis .................................................... 188<br />
APPENDIX VII: Copy <strong>of</strong> UBC Research Ethics Board certificate <strong>of</strong> approval........................... 189<br />
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