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Interpreting translocations detected by paired-end sequencing of cancer samples
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Molecular Cancer Genetics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2012 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105Article in journal (Refereed) Submitted
Place, publisher, year, edition, pages
2012.
National Category
Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
URN: urn:nbn:se:uu:diva-182309OAI: oai:DiVA.org:uu-182309DiVA: diva2:559448
Available from: 2012-10-09 Created: 2012-10-09 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Somatic Mutations in Breast Cancer Genomes: Discovery and Validation of Breast Cancer Genes
Open this publication in new window or tab >>Somatic Mutations in Breast Cancer Genomes: Discovery and Validation of Breast Cancer Genes
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 822
Keyword
breast cancer, cancer gene, pathway, somatic mutation, structural alteration, sequencing, whole genome amplification
National Category
Medical Genetics Genetics
Research subject
Genetics; Medical Genetics
Identifiers
urn:nbn:se:uu:diva-182319 (URN)978-91-554-8490-3 (ISBN)
Public defence
2012-11-21, Rudbecksalen, Dag Hammarskjölds v 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-10-31 Created: 2012-10-09 Last updated: 2013-01-23Bibliographically approved

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Jiao, XiangTellgren-Roth, ChristianCavelier, LuciaSjöblom, Tobias

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