Chapter 2 - University of British Columbia

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cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines. Ann Oncol 2008, 19(6):1053-1059. 36. Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J, Henderson JM, Kutok JL, Rajewsky K: Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol 2008, 9(4):405-414. 37. Lee RC, Ambros V: An extensive class of small RNAs in Caenorhabditis elegans. Science 2001, 294(5543):862-864. 38. Mattick JS, Makunin IV: Small regulatory RNAs in mammals. Hum Mol Genet 2005, 14 Spec No 1:R121-132. 39. McManus MT: MicroRNAs and cancer. Semin Cancer Biol 2003, 13(4):253-258. 40. Vasudevan S, Tong Y, Steitz JA: Switching from repression to activation: microRNAs can up-regulate translation. Science 2007, 318(5858):1931-1934. 173
APPENDIX I: List of publications This appendix details all of the publications that I was a part of that were either published, accepted, currently in submission, or prepared for submission. In total, 29 publications are listed below with four of them represented as chapters and an additional nine discussed in section 1.11. The remaining 16 publications are listed below with a brief description accompanying each publication. Publications included as thesis chapters 1. Chari R, Coe BP, Wedseltoft C, Benetti M, Wilson IM, Vucic E, MacAulay C, Ng RT, Lam WL. (2008) SIGMA2: A system for the integrative genomic multi-dimensional analysis of cancer genomes, epigenomes, and transcriptomes. BMC Bioinformatics, 9(1):422, 1-12. This publication is included in the thesis as chapter 2. 2. Chari R, Coe BP, Vucic EA, Lockwood WW, Lam WL. (2010) An integrative multi- dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer. BMC Systems Biology. Submitted. This manuscript submitted for publication is included in the thesis as chapter 3. 3. Chari R, Lockwood WW, Coe BP, Soh J, MacAulay C, Lam S, Gazdar AF, Lam WL. (2010) UPD is a frequent mechanism of gene disruption in lung adenocarcinoma. This manuscript in preparation is included in the thesis as chapter 4. 4. Chari R, Thu KL, Wilson IM, Lockwood WW, Lonergan KM, Coe BP, Malloff CA, Gazdar AF, Lam S, Garnis C, MacAulay CE, Alvarez CE, Lam WL. (2010) Integrating the multiple dimensions of genomic and epigenomic landscapes of cancer. Cancer and Metastasis Reviews, 29(1):73-93. 174
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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
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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
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 and 148: Figure 5.4. Integration of copy num
Page 149 and 150: Figure 5.5. 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: 16. Zhang K, Li JB, Gao Y, Egli D,
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
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Page 199 and 200: APPENDIX III: Sources of data Sampl
Page 201 and 202: APPENDIX V: Kaplan-Meier and Oncomi
Page 203 and 204: APPENDIX VI: Summary of Kaplan-Meie
Page 205: University of British Columbia - Br
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