Chapter 2 - University of British Columbia

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Figure 5.4 a b c d # of copies # of copies 4 2 0 3 2 1 0 Normal Tumor Relative expression 7000 6000 5000 4000 3000 2000 1000 0 Total copy number: Ampli�cation Allele speci�c copy number DNA hypomethylation Overexpression MUC1 Normal Tumor 133
Figure 5.5. Integration of copy number, allelic status, DNA methylation, and gene expression for a single lung adenocarcinoma sample. Enhanced analysis of the cancer phenotype using an integrative and multi-dimensional approach. (a) On average, a higher proportion of differential gene expression can be associated with genomic alterations when examining multiple DNA dimensions relative to single dimensions. (b) Using a fixed frequency threshold of 50 %, more genes are revealed to be frequently disrupted when multiple mechanisms of genomic alteration (e.g. altered copy number, DNA methylation, or copy number neutral LOH) are considered, (~200 genes versus more than 1000 genes). (c) Pathway analyses performed using gene lists derived from a multi-dimensional approach, identifies an enhanced number of aberrant pathways relative to those identified from a uni-dimensional approach. (d) Functional pathways identified using the integrated gene list are of relatively high significance; the top 10 such pathways are shown. This suggests that the additional identified genes associate with specific pathways rather than with random functions. The four bars represent, from left to right: all dimensions, copy number, DNA methylation, and UPD. Ingenuity Pathway Analysis was used for analyses in (c) and (d). (e) Example of two genes that are missed when a single DNA dimension is studied, but captured when multiple DNA dimensions are examined. Both ribonucleotide reductase M2 (RRM2) [279, 280] and retinoic acid receptor responder (tazarotene induced) 2 (RARRES2) [281, 282] are known to be deregulated in multiple cancer types. 134
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DEVELOPMENT AND APPLICATION OF AN I
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Table of Contents Abstract ........
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3.3.2 Multi-dimensional analysis (M
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List of Tables Table 2.1. Features
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Figure 5.3. Overlay of chromosomal
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RB1 Retinoblastoma 1 RNA Ribonuclei
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Dedication To my family. xiii
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Chapter 5: Chari R, Thu KL, Wilson
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1.1 Lung cancer Lung cancer has the
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expression changes are reactive to
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number of different cancer types. M
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large number of tumors, that a give
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(B) By using an integrative approac
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platforms, with one of the latest s
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1.12.1 Development of tools for gen
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quantitative PCR experiments as wel
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1.13 References 1. Jemal A, Siegel
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33. Garber ME, Troyanskaya OG, Schl
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71. Shivapurkar N, Gazdar AF: DNA M
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Chapter 2: SIGMA 2 : A system for t
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Here, we present SIGMA 2 , a novel
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datasets. To utilize this, the user
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2.3.7 Analysis of data from multipl
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expression (Figure 2.8). ERBB2 has
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Figure 2.1 R -Segmentation -Statist
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Figure 2.3 numSamples
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Figure 2.5. Consensus calling and h
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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
Page 97 and 98: 4.2.3 Determining frequent regions
Page 99 and 100: etween loss and UPD (Figure 4.3). S
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Page 103 and 104: Figure 4.1. Detection of UPD using
Page 105 and 106: Figure 4.2. Comparison of frequent
Page 107 and 108: Figure 4.3 Gain Loss 642 441 7 Figu
Page 109 and 110: 94 Figure 4.4 1 2 3 4 5 6 7 8 9 10
Page 111 and 112: Figure 4.6 a b c Percent of cases A
Page 113 and 114: Figure 4.7 a b 6p25.3 Log2 fold cha
Page 115 and 116: Chr BPStart BPEnd # of Chr BPStart
Page 117 and 118: Table 4.3. Overlap of oncogenes in
Page 119 and 120: Table 4.5. Cell lines and oncogene
Page 121 and 122: Table 4.7. RefSeq genes in focal re
Page 123 and 124: 4.6 References 1. Bell DW: Our chan
Page 125 and 126: 33. Garnis C, Coe BP, Lam SL, MacAu
Page 127 and 128: 5.1 Introduction In the past decade
Page 129 and 130: polymorphism (SNP) arrays with over
Page 131 and 132: substitutions) and UV exposure (C t
Page 133 and 134: developed antibodies and methylated
Page 135 and 136: Histone modification states. While
Page 137 and 138: metastasis [226]. High throughput a
Page 139 and 140: Implications on sample size require
Page 141 and 142: analyzed using the "minet" package
Page 143 and 144: expression. The next challenge is t
Page 145 and 146: Figure 5.2 # of copies Total copy n
Page 147: Figure 5.4. Integration of copy num
Page 151 and 152: Figure 5.6 SHC1 GRB2 SOS2 RRAS ER R
Page 153 and 154: Figure 5.8 a Log2 Fold Change (T vs
Page 155 and 156: Figure 5.10 (a) (b) Figure 5.10. Au
Page 157 and 158: Table 5.2. List of genomic resource
Page 159 and 160: 5.5 References 1. Pinkel D, Segrave
Page 161 and 162: 37. Oliphant A, Barker DL, Stuelpna
Page 163 and 164: 75. Selzer RR, Richmond TA, Pofahl
Page 165 and 166: 111. Melcher R, Al-Taie O, Kudlich
Page 167 and 168: 145. Takai D, Yagi Y, Wakazono K, O
Page 169 and 170: 179. Kondo M, Suzuki H, Ueda R, Osa
Page 171 and 172: alterations in human prostate cance
Page 173 and 174: 248. Xi L, Feber A, Gupta V, Wu M,
Page 175 and 176: 281. Fernandez-Ranvier GG, Weng J,
Page 177 and 178: Chapter 6: Conclusions 162
Page 179 and 180: can identify nearly three times as
Page 181 and 182: was identified in a small set of sa
Page 183 and 184: will be done at the pathway level a
Page 185 and 186: previously described genetic and ep
Page 187 and 188: 16. Zhang K, Li JB, Gao Y, Egli D,
Page 189 and 190: APPENDIX I: List of publications Th
Page 191 and 192: This publication is described in se
Page 193 and 194: This chapter details the technologi
Page 195 and 196: epigenetic alteration. This led to
Page 197 and 198: 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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