Chapter 2 - University of British Columbia

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5.2 Genomic alterations ........................................................................................................ 113 5.2.1 Chromosomal aberrations ........................................................................................ 113 5.2.2 Gene dosage, allelic imbalance, mutational status ................................................... 113 5.2.3 Genomic landscape: Gains, losses and uniparental disomy .................................... 116 5.3 Epigenomic alterations .................................................................................................... 117 5.3.1 The cancer methylome ............................................................................................. 117 5.3.2 Integration of cancer genomic and epigenomic events ............................................ 119 5.4 Relating genetic and epigenetic events to changes in the transcriptome through integrative analysis ................................................................................................................ 120 5.4.1 Multiple mechanisms of gene disruption ................................................................... 121 5.4.2 Multiple mechanisms of disrupting non-coding RNA levels ...................................... 121 5.4.3 Multi-dimensional integration of genome, epigenome, and transcriptome ............... 122 5.4.4 Disruption of multiple components in biological pathways ........................................ 124 5.4.5 Identification of a novel gene involved with EGFR signaling deregulated in adenocarcinoma ................................................................................................................ 125 5.4.6 Prevalence of SIRPA deregulation and association with clinical characteristics ...... 126 5.5 Tracking clonal expansion in spatial dimensions ............................................................ 127 5.6 Evaluating the biological significance of integrative genomics findings .......................... 127 5.5 References ...................................................................................................................... 144 Chapter 6: Conclusions ............................................................................................................. 162 6.1 Summary ......................................................................................................................... 163 6.1.1 Development of the integrative genetic and epigenetic approach ............................ 163 6.1.2 Identification of a prevalent genetic alteration in lung adenocarcinoma ................... 164 6.1.3 Application of the integrative approach to lung adenocarcinoma specimens ........... 165 6.2 Conclusions ..................................................................................................................... 166 6.3 Future directions .............................................................................................................. 168 6.4 References ...................................................................................................................... 171 APPENDIX I: List of publications .............................................................................................. 174 APPENDIX II: Description of cell lines ...................................................................................... 183 APPENDIX III: Sources of data ................................................................................................. 184 APPENDIX IV: MCD strategy and Kaplan-Meier analysis of TUSC3 ....................................... 185 APPENDIX V: Kaplan-Meier and Oncomine expression analysis of frequent MCD genes ...... 186 APPENDIX VI: Summary of Kaplan-Meier survival analysis .................................................... 188 APPENDIX VII: Copy of UBC Research Ethics Board certificate of approval........................... 189 vi
List of Tables Table 2.1. Features required for integrative analysis .................................................................. 44 Table 2.2. Summary of Input, analysis, output for each dimension ............................................ 45 Table 4.1. Regions of the genome exhibiting frequent UPD ....................................................... 99 Table 4.2. List of major oncogenes and tumor suppressor genes assessed ............................ 101 Table 4.3. Overlap of oncogenes in frequent regions of genomic alteration ............................. 102 Table 4.4. Overlap of tumor suppressor genes in frequent regions of genomic alteration ....... 103 Table 4.5. Cell lines and oncogene loci with homozygous mutation ......................................... 104 Table 4.6. Summary of homozygous mutation analysis in cancer cell lines ............................. 105 Table 4.7. RefSeq genes in focal regions of UPD .................................................................... 106 Table 4.8. Genes overexpressed in focal regions of UPD ........................................................ 107 Table 5.1. List of software for integrative analysis .................................................................... 141 Table 5.2. List of genomic resources and databases ............................................................... 142 Table 5.3. Genes interacting with SIRPA as identified by network analysis ............................. 143 vii
Page 1 and 2: DEVELOPMENT AND APPLICATION OF AN I
Page 3 and 4: Table of Contents Abstract ........
Page 5: 3.3.2 Multi-dimensional analysis (M
Page 9 and 10: Figure 5.3. Overlay of chromosomal
Page 11 and 12: RB1 Retinoblastoma 1 RNA Ribonuclei
Page 13 and 14: Dedication To my family. xiii
Page 15 and 16: Chapter 5: Chari R, Thu KL, Wilson
Page 17 and 18: 1.1 Lung cancer Lung cancer has the
Page 19 and 20: expression changes are reactive to
Page 21 and 22: number of different cancer types. M
Page 23 and 24: large number of tumors, that a give
Page 25 and 26: (B) By using an integrative approac
Page 27 and 28: platforms, with one of the latest s
Page 29 and 30: 1.12.1 Development of tools for gen
Page 31 and 32: quantitative PCR experiments as wel
Page 33 and 34: 1.13 References 1. Jemal A, Siegel
Page 35 and 36: 33. Garber ME, Troyanskaya OG, Schl
Page 37 and 38: 71. Shivapurkar N, Gazdar AF: DNA M
Page 39 and 40: Chapter 2: SIGMA 2 : A system for t
Page 41 and 42: Here, we present SIGMA 2 , a novel
Page 43 and 44: datasets. To utilize this, the user
Page 45 and 46: 2.3.7 Analysis of data from multipl
Page 47 and 48: expression (Figure 2.8). ERBB2 has
Page 49 and 50: Figure 2.1 R -Segmentation -Statist
Page 51 and 52: Figure 2.3 numSamples
Page 53 and 54: Figure 2.5. Consensus calling and h
Page 55 and 56: Figure 2.6 HCC2218 HCC2218 HCC2218B
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Figure 2.8. Multi-dimensional persp
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Table 2.1. Features required for in
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2.6 References 1. Garnis C, Buys TP
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Chapter 3: An integrative multi-dim
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observed gene expression deregulati
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Raw gene expression profiles from a
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screening approach to gene amplific
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many regions of frequent LOH/AI do
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approach to examining the whole gen
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PTEN expression [44]. Using this pa
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mechanisms at the DNA and RNA level
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In this study, three DNA dimensions
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Figure 3.2. Quantitative and qualit
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Figure 3.3 a Proportion of genes in
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70 Figure 3.5 -log(pvalue) 5.0 4.0
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72 Figure 3.7 Sample: HCC1008 Copy
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Figure 3.8 a b Proportion of random
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16. Chari R, Lockwood WW, Coe BP, C
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50. Giovane A, Pintzas A, Maira SM,
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4.1 Introduction Genetic alteration
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4.2.3 Determining frequent regions
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etween loss and UPD (Figure 4.3). S
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obtained, profiled and used as the
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Figure 4.1. Detection of UPD using
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Figure 4.2. Comparison of frequent
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Figure 4.3 Gain Loss 642 441 7 Figu
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94 Figure 4.4 1 2 3 4 5 6 7 8 9 10
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Figure 4.6 a b c Percent of cases A
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Figure 4.7 a b 6p25.3 Log2 fold cha
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Chr BPStart BPEnd # of Chr BPStart
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Table 4.3. Overlap of oncogenes in
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Table 4.5. Cell lines and oncogene
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Table 4.7. RefSeq genes in focal re
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4.6 References 1. Bell DW: Our chan
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33. Garnis C, Coe BP, Lam SL, MacAu
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5.1 Introduction In the past decade
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polymorphism (SNP) arrays with over
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substitutions) and UV exposure (C t
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developed antibodies and methylated
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Histone modification states. While
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metastasis [226]. High throughput a
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Implications on sample size require
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analyzed using the "minet" package
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expression. The next challenge is t
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Figure 5.2 # of copies Total copy n
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Figure 5.4. Integration of copy num
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Figure 5.5. Integration of copy num
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Figure 5.6 SHC1 GRB2 SOS2 RRAS ER R
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Figure 5.8 a Log2 Fold Change (T vs
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Figure 5.10 (a) (b) Figure 5.10. Au
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Table 5.2. List of genomic resource
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5.5 References 1. Pinkel D, Segrave
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37. Oliphant A, Barker DL, Stuelpna
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75. Selzer RR, Richmond TA, Pofahl
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111. Melcher R, Al-Taie O, Kudlich
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145. Takai D, Yagi Y, Wakazono K, O
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179. Kondo M, Suzuki H, Ueda R, Osa
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alterations in human prostate cance
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248. Xi L, Feber A, Gupta V, Wu M,
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281. Fernandez-Ranvier GG, Weng J,
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Chapter 6: Conclusions 162
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can identify nearly three times as
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was identified in a small set of sa
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will be done at the pathway level a
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previously described genetic and ep
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16. Zhang K, Li JB, Gao Y, Egli D,
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APPENDIX I: List of publications Th
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This publication is described in se
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This chapter details the technologi
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epigenetic alteration. This led to
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This manuscript describes the curre
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APPENDIX III: Sources of data Sampl
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APPENDIX V: Kaplan-Meier and Oncomi
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APPENDIX VI: Summary of Kaplan-Meie
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University of British Columbia - Br
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Chapter 2 - University of British Columbia

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