Chapter 2 - University of British Columbia

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95 Figure 4.5 a chr12 (p12.1-p11.21) 12q12 15 22 b 85060201 85070205 85070159 85060358 85050147 85060186 85050235 85070021 85070093 85060276 85050241 85040031 85060354 85060256 85050172 85040001 85050140 85060342 85060206 85060311 85060251 85050207 85060098 85070205 85060186 85060098 85060342 85060251 85050177 85070081 85050011 85060358 85060256 85050147 85040001 85060221 85070085 85060216 85060068 85050172 85070061 85060311 85070093 85040031 KRAS KRAS UPD Regions chr13 (q13.3-q21.1) 13 p12 11.2 21.1 q31.1 q34 RB1 UPD Regions Figure 4.5. Examination of UPD events at the KRAS and RB1 loci. KRAS shown in (a) and RB1 shown in (b). The region of UPD encompassing these loci varies in size between samples, with some samples illustrating larger sizes of UPD than others. The existence of these different size events are likely a result of a different underlying mechanism of UPD. RB1
Figure 4.6 a b c Percent of cases All Genes (n=67) KRAS (n=33) BRAF (n=11) Gain Loss UPD Neutral 50 KRAS (n=21) 40 30 20 10 0 Gain UPD Loss Neutral # of copies # of alleles # of copies # of alleles 3 2 1 0 4 2 0 3 2 1 0 4 2 0 A427 Chromosome 7 BRAF NCI-H2030 KRAS Chromosome 12 Figure 4.6. Relationship of homozygous mutation at oncogenes and genomic alteration. Using the Wellcome Trust Sanger COSMIC database for somatic mutation data and SNP 6.0 data available for over 700 cancer cell lines from their database, prevalence of UPD was assessed in this dataset. Specifically, only those cell lines with oncogenes and homozygous mutation were analyzed. (a) In total, 67 instances of homozygous mutation at an oncogene loci were identified. While a large fraction of cases exhibited copy number increase (51%), the second most prominent alteration is UPD (34%). Of the 12 different genes assessed, KRAS and BRAF are the most frequently homozygously mutated oncogenes and those two genes show similar frequency distribution patterns of genomic alteration to the whole set. (b) An example of UPD at BRAF in A427 and KRAS in NCI-H2030 where both BRAF and KRAS are homozygously mutated. (c) With available mutation data on KRAS from the 46 lung tumor/matched non-malignant tissue pairs, similar analysis was performed and it was found that the patterns of genomic alteration were similar to what was observed in cancer cell lines. 96 Allele Speci�c Copy Number Total Copy Number Allele Speci�c Copy Number Total Copy Number
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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
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
Page 65 and 66: observed gene expression deregulati
Page 67 and 68: Raw gene expression profiles from a
Page 69 and 70: screening approach to gene amplific
Page 71 and 72: many regions of frequent LOH/AI do
Page 73 and 74: approach to examining the whole gen
Page 75 and 76: PTEN expression [44]. Using this pa
Page 77 and 78: mechanisms at the DNA and RNA level
Page 79 and 80: In this study, three DNA dimensions
Page 81 and 82: Figure 3.2. Quantitative and qualit
Page 83 and 84: Figure 3.3 a Proportion of genes in
Page 85 and 86: 70 Figure 3.5 -log(pvalue) 5.0 4.0
Page 87 and 88: 72 Figure 3.7 Sample: HCC1008 Copy
Page 89 and 90: Figure 3.8 a b Proportion of random
Page 91 and 92: 16. Chari R, Lockwood WW, Coe BP, C
Page 93 and 94: 50. Giovane A, Pintzas A, Maira SM,
Page 95 and 96: 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
Page 101 and 102: obtained, profiled and used as the
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
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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 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
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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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