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Molecular Genetic Characterization of Retinoblastoma Tumors Lacking Rb1 Mutations

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Molecular Genetic Characterization of Retinoblastoma Tumors Lacking Rb1 Mutations MOLECULAR GENETIC CHARACTERIZATION OF RETINOBLASTOMA TUMORS LACKING RB1 MUTATIONS by Jennifer Yvonne Kennett B.Sc., Simon Fraser University, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in The Faculty Of Graduate Studies (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2012 © Jennifer Yvonne Kennett, 2012 Abstract Retinoblastoma is a rare childhood cancer of the retina and is the most common intraocular tumor in children. Classically, retinoblastoma results from biallelic loss of the RB1 tumor suppressor gene. As with other cancer types, dysregulation of a single gene alone is not considered sufficient for complete transformation to malignancy. Frequent regions of genetic alteration harbouring additional genes, implicated in retinoblastoma oncogenesis and progression, include chromosomes 1q, 2p, 6p, 13q and 16q. Sensitive molecular genetic screening techniques are capable of identifying RB1 mutations in 98% of unilateral retinoblastoma tumors. The remaining 2% harbour no identifiable RB1 inactivating alterations, and therefore molecular interrogation of these cases would likely reveal alternative genetic events driving retinoblastoma tumorigenesis in the absence of RB1 inactivation. Towards this objective, in this thesis work, I describe genetic alterations identified by tiling path array comparative genomic hybridization in a rare sample set composed of 23 RB1+/+ tumors. In addition to gene disruption by copy number alteration, mechanisms of gene disruption resulting in no overall change in copy number or change in copy number with allelic imbalance were also investigated utilizing genome-wide SNP array analysis on five of the RB1+/+ tumors. The most striking recurrent genetic alteration identified in retinoblastoma tumors lacking RB1 inactivating mutations, was focal high-level MYCN amplification, which occurred at a frequency of approximately 48%. The MYCN amplified RB1+/+ tumors also exhibited a statistically significant lower proportion of their genome affected by genomic instability when compared with the RB1-/- tumors. In a subset of five matched tumor and blood normal samples the occurrence of copy neutral LOH was explored, although none was observed. Allele specific copy number analysis identified instances of allelic imbalance, including all five MYCN amplifications. Amplification of MYCN may represent a rare and novel alternate mechanism of retinoblastoma tumorigenesis. This work provides insight into the role of mutational events driving tumorigenesis in retinoblastoma in the absence of RB1 inactivation. ii Preface Chapters 2 and 3 are based on work conducted with Dr. Brenda Gallie, Diane Rushlow, and Stephanie Yee of The Ontario Cancer Institute and The Toronto Western Hospital Research Institute. I was responsible for performing array CGH experiments, generating copy number profiles, identifying frequently altered regions and genes including identifying MYCN amplification as the most frequent event and defining the minimal region of amplification, as well as performing statistical and pathway analyses for all of the data presented in this thesis. I am co-second author of a manuscript in preparation describing the findings presented in this thesis, in addition to QmPCR, histology, immunohistochemistry and functional work conducted by Diane Rushlow et al. This research was approved by the British Columbia Cancer Agency Research Ethics Board – Clinical, Ethics Certificate R05-1072. iii Table of Contents Abstract .................................................................................................................................... ii Preface ..................................................................................................................................... iii Table of Contents ................................................................................................................... iv List of Tables ......................................................................................................................... vii List of Figures ....................................................................................................................... viii List of Abbreviations ............................................................................................................. ix Acknowledgements ............................................................................................................... xii Dedication ............................................................................................................................. xiii 1 Chapter: Introduction ...................................................................................................... 1 1.1 Retinoblastoma ..................................................................................................................... 1 1.1.1 Incidence and occurrence ................................................................................................. 1 1.1.2 Diagnosis and treatment ................................................................................................... 2 1.1.3 Hereditary and nonhereditary forms of retinoblastoma .................................................... 2 1.2 Retinoblastoma genetics ....................................................................................................... 3 1.2.1 Discovery of tumor suppressor class of genes .................................................................. 3 1.2.2 RB1 gene and pRB ............................................................................................................ 3 1.2.3 Cell models of retinoblastoma .......................................................................................... 5 1.2.4 Mouse models of retinoblastoma ...................................................................................... 6 1.2.5 Copy number alterations and cancer ................................................................................. 7 1.2.6 Array comparative genomic hybridization ....................................................................... 7 1.2.7 Genotyping arrays ............................................................................................................. 8 1.2.8 Common genetic alterations in retinoblasoma in addition to RB1 ................................... 9 1.2.9 Gain of 1q ....................................................................................................................... 10 1.2.10 Gain of 2p and MYCN amplification .......................................................................... 11 1.2.11 Gain of 6p ................................................................................................................... 11 1.2.12 Copy number alterations on 13q ................................................................................ 12 1.2.13 Loss of 16q ................................................................................................................. 12 1.2.14 Retinoblastoma molecular genetic testing .................................................................. 13 iv 1.3 Hypotheses and research questions ..................................................................................... 14 1.3.1 Research questions.......................................................................................................... 14 1.3.2 First hypothesis ............................................................................................................... 14 1.3.3 Second hypothesis .......................................................................................................... 14 1.3.4 Third hypothesis ............................................................................................................. 15 2 Chapter: Materials and Methods .................................................................................. 16 2.1 Samples ............................................................................................................................... 16 2.1.1 Sample DNA ................................................................................................................... 16 2.1.2 RB1 gene mutation status ................................................................................................ 16 2.1.3 Incidence of RB1+/+ retinoblastoma across the four testing sites .................................... 17 2.2 Whole-genome sub-megabase resolution tiling path aCGH analysis ................................. 17 2.2.1 Array CGH data analysis ................................................................................................ 18 2.2.2 Segmentation and alteration detection criteria ................................................................ 19 2.2.3 Identification of frequent regions of copy number alteration ......................................... 19 2.2.4 Definition of gains and high-level amplifications .......................................................... 20 2.2.5 Determination of proportion of the genome altered ....................................................... 21 2.2.6 Statistical comparison of data means between two groups ............................................. 22 2.2.7 Network/ pathway level analysis of altered genes .......................................................... 22 2.3 Affymetrix genome-wide SNP 6.0 array Genotyping ......................................................... 23 2.3.1
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