Chapter 2 - University of British Columbia

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Co-Authorship Statement Chapters 2 to 5 were co-authored as manuscripts for publication. The following author lists apply for each chapter: Chapter 2: Chari R, Coe BP, Wedseltoft C, Benetti M, Wilson IM, Vucic EA, 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. Contribution: I am the first author of this manuscript. I designed and developed the software and wrote the manuscript. The co-authors of this manuscript were either undergraduate students who I mentored on this project or were fellow graduate students who tested the software and provided important user feedback. Chapter 3: Chari R, Coe BP, Vucic EA, Lockwood WW, Lam WL. (2010) An integrative multidimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer. BMC Systems Biology, 4(1):67, 1-14. Contribution: I am the first author of this manuscript. I acquired most of the data through generating genomic profiles and downloaded the rest of the data from public resources. I conceived the analysis for the manuscript and wrote the manuscript. Chapter 4: Chari R, Lockwood WW, Soh J, Coe BP, Tam K, MacAulay C, Minna JD, Lam S, Gazdar AF, Lam WL. (2010) Uniparental disomy is a prevalent mechanism of genetic alteration in lung adenocarcinoma. Contribution: I am the first author of this manuscript. I generated all of the data and performed all of the analyses for this manuscript and my co-authors provided useful information through comments and other supporting data. xiv
Chapter 5: 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. Contribution: I am the first author of this manuscript. I orchestrated the study, performed all analyses and wrote the manuscript with the help of my supervisor. Other co-authors provided useful information, data, or comments. xv
Page 1 and 2: DEVELOPMENT AND APPLICATION OF AN I
Page 3 and 4: Table of Contents Abstract ........
Page 5 and 6: 3.3.2 Multi-dimensional analysis (M
Page 7 and 8: List of Tables Table 2.1. Features
Page 9 and 10: Figure 5.3. Overlay of chromosomal
Page 11 and 12: RB1 Retinoblastoma 1 RNA Ribonuclei
Page 13: Dedication To my family. xiii
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
Page 57 and 58: Figure 2.8. Multi-dimensional persp
Page 59 and 60: Table 2.1. Features required for in
Page 61 and 62: 2.6 References 1. Garnis C, Buys TP
Page 63 and 64: 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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