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Discovery and Validation of Breast Cancer Genes

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Discovery and Validation of Breast Cancer Genes Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 822 Somatic Mutations in Breast Cancer Genomes Discovery and Validation of Breast Cancer Genes XIANG JIAO ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-8490-3 UPPSALA urn:nbn:se:uu:diva-182319 2012 Dissertation presented at Uppsala University to be publicly examined in Rudbecksalen, Dag Hammarskjölds v 20, Uppsala, Wednesday, November 21, 2012 at 09:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Abstract Jiao, X. 2012. Somatic Mutations in Breast Cancer Genomes: Discovery and Validation of Breast Cancer Genes. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 822. 53 pp. Uppsala. ISBN 978-91-554-8490-3. Breast cancer is the most common cancer in women worldwide. However, the genetic alterations that lead to breast cancer are not fully understood. This thesis aims to identify novel genes of potential mechanistic, diagnostic or therapeutic interest in breast cancers by mutational analysis and whole-genome sequencing. In paper I, sequencing of 36 previously identified candidate genes in 96 breast tumors with patient-matched normal DNA determined the somatic mutation prevalence of these candidate genes and identified additional mutations in Notch, NF-κB, PI3K, and Hedgehog pathways as well as in processes mediating DNA methylation, RNA processing and calcium signaling. In paper II, comparison of massively parallel mate-pair sequencing results of a human genome before and after phi29-mediated multiple displacement amplification (MDA) revealed that MDA introduces structural alteration artifacts, with an emphasis on false positive inversions, and impairs the sensitivity to detect true inversions. Therefore, MDA has limited value in sample preparation for whole-genome sequencing for structural alteration detection. In paper III, massively parallel paired-end sequencing identified gene rearrangements in 15 hormone receptor negative breast cancers. Forty validated rearrangements were predicted to directly affect 30 genes, involved in epigenetic regulation, cell mitosis, signalling transduction and glycolytic flux. RNA interference-based assays revealed the potential roles in cell growth of some affected genes, among which DDX10 was implicated to be involved in apoptosis. In paper IV, a method for statistical evaluation of putative translocations detected by massively parallel paired-end sequencing was proposed. In an application of this method to analyse translocations detected by cancer genome deep paired-end sequencing, 76 putative translocations were classified into four categories, with the majority likely to be caused by mismapping due to repetitive regions. Taken together, this thesis provides insights into genes and pathways mutated in sporadic breast cancer genomes, which broaden our understanding of the genetic basis of breast cancer and may ultimately facilitate the diagnosis and treatment of this disease. Keywords: breast cancer, cancer gene, pathway, somatic mutation, structural alteration, sequencing, whole genome amplification Xiang Jiao, Uppsala University, Department of Immunology, Genetics and Pathology, Rudbecklaboratoriet, SE-751 85 Uppsala, Sweden. © Xiang Jiao 2012 ISSN 1651-6206 ISBN 978-91-554-8490-3 urn:nbn:se:uu:diva-182319 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-182319) Dedicated to my family 献给我的家人 List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Jiao, X., Wood, L.D., Lindman, M., Jones, S., Buckhaults, P., Polyak, K., Sukumar, S., Carter, H., Kim, D., Karchin, R. and Sjöblom, T. (2012) Somatic mutations in the Notch, NF-KB, PIK3CA, and Hedgehog pathways in human breast cancers. Genes Chromosomes Cancer, 51(5):480–489 II Jiao, X., Rosenlund, M., Hooper, S.D., Tellgren-Roth, C., He, L., Fu, Y., Mangion, J. and Sjöblom, T. (2011) Structural altera- tions from multiple displacement amplification of a human ge- nome revealed by mate-pair sequencing. PLoS ONE, 6(7): e22250 III Hooper, S.D.*, Jiao, X.*, Djureinovic, T., Larsson, C., Wärn- berg, F., Tellgren-Roth, C., Botling, J. and Sjöblom, T. Gene rearrangements in hormone receptor negative breast cancers re- vealed by paired-end sequencing. Submitted IV Hooper, S.D., Jiao, X., Rosenlund, M., Tellgren-Roth, C., Cavelier, L. and Sjöblom, T. Interpreting translocations detect- ed by paired-end sequencing of cancer samples. Submitted *These authors contributed equally to this work. Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 The cancer genome ................................................................................... 11 Genome instability as a driver of tumor development ......................... 11 Cancer genes and pathways ................................................................. 12 Technologies to characterize cancer genomes ......................................... 13 Identification of cancer genes prior to the completion of the human genome sequence ................................................................................. 14 New insights into cancer genomics from the completion of the human genome sequence ..................................................................... 14 Massively parallel sequencing technology in cancer genomics .......... 15 The landscape of cancer genomes ............................................................ 17 Breast cancer ............................................................................................ 24 Epidemiology and etiology .................................................................. 24 Pathology and staging .......................................................................... 24 Subtypes and targeted therapy ............................................................. 26 Genomic landscapes ............................................................................ 26 Present Investigation ..................................................................................... 29 Aims ......................................................................................................... 29 Results and discussion .............................................................................. 29 Paper I Genes in Notch, NF-κB, PI3K, and Hedgehog pathways are somatically mutated in human breast cancers ................................ 29 Paper II Phi29-mediated multiple displacement amplification introduces false positive structural alterations detected by whole- genome sequencing .............................................................................. 32 Paper III Somatic gene rearrangements in hormone receptor negative breast cancers ........................................................................ 33 Paper IV Statistical evaluation and interpretation of putative translocations detected by massively parallel paired-end sequencing . 35 Concluding remarks and future perspectives ................................................ 36 Appendix ....................................................................................................... 38 Acknowledgements ....................................................................................... 41 References ..................................................................................................... 43 Abbreviations AJCC American Joint Committee on Cancer CAN-genes Candidate cancer genes CGH Comparative genomic hybridization CGP Cancer Genome Project CHASM Cancer-specific high-throughput annotation of somatic mutations CIN Chromosome instability DCIS Ductal carcinoma in situ ER Estrogen receptor HD Homozygous deletion HER2 Human epidermal growth factor receptor 2 HNPCC Hereditary non-polyposis colon cancer HR Hormone receptor ICGC International Cancer Genome Consortium IDC Invasive ductal carcinoma IHC Immunohistochemistry ILC Invasive lobular carcinoma LOH Loss of heterozygosity MDA Multiple displacement amplification MIN Microsatellite instability MMR Mismatch repair mTOR Mechanistic target of rapamycin MuSiC Mutational significance in cancer PCR Polymerase chain reaction PI3K Phosphoinositide 3-kinase PolyPhen Polymorphism phenotyping PR Progesterone receptor PTK Protein tyrosine kinase PTP Protein tyrosine phosphatase RTK Receptor tyrosine kinase SIFT Sorting intolerant from tolerant TCGA The Cancer Genome Atlas TNBC Triple negative breast cancer WHO World Health Organization Introduction The cancer genome Cancer is, essentially, a genetic disease caused by a series of alterations in genes that control cell growth and proliferation. These alterations can be in the form of changes of one or a few nucleotides, such as point mutations, or displacements of larger DNA segments, namely structural alterations. Struc- tural alterations include translocations, inversions and copy number varia- tions caused by insertions, duplications and deletions. Mutations in cancer genomes are either constitutional or somatic. Constitutional mutations are inherited from a parent and cause hereditary susceptibility to cancer, whereas somatic mutations occur later in tumor development and result in sporadic tumors. In addition, epigenetic alterations that lead to up- and down- regulation of gene expression occur in most cancers 1-2. Genome instability as a driver
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