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Somatic Mutations in Breast Cancer Genomes: Discovery and Validation of Breast Cancer Genes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Molecular Cancer Genetics)
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 [en]
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: urn:nbn:se:uu:diva-182319ISBN: 978-91-554-8490-3 (print)OAI: oai:DiVA.org:uu-182319DiVA: diva2:559456
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
List of papers
1. Somatic mutations in the notch, NF-KB, PIK3CA, and hedgehog pathways in human breast cancers
Open this publication in new window or tab >>Somatic mutations in the notch, NF-KB, PIK3CA, and hedgehog pathways in human breast cancers
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2012 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 51, no 5, 480-489 p.Article in journal (Refereed) Published
Abstract [en]

Exome sequencing of human breast cancers has revealed a substantial number of candidate cancer genes with recurring but infrequent somatic mutations. To determine more accurately their mutation prevalence, we performed a mutation analysis of 36 novel candidate cancer genes in 96 human breast cancers. Somatic mutations with potential impact on protein function were observed in the genes ADAM12, CENTB1, CENTG1, DIP2C, GLI1, GRIN2D, HDLBP, IKBKB, KPNA5, NFKB1, NOTCH1, and OTOF. These findings strengthen the evidence for involvement of the Notch, Hedgehog, NF-KB, and PIK3CA pathways in breast cancer development, and point to novel processes that likely are involved.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-172019 (URN)10.1002/gcc.21935 (DOI)000301118100008 ()
Available from: 2012-04-02 Created: 2012-04-01 Last updated: 2017-12-07Bibliographically approved
2. Structural Alterations from Multiple Displacement Amplification of a Human Genome Revealed by Mate-Pair Sequencing
Open this publication in new window or tab >>Structural Alterations from Multiple Displacement Amplification of a Human Genome Revealed by Mate-Pair Sequencing
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, e22250- p.Article in journal (Refereed) Published
Abstract [en]

Comprehensive identification of the acquired mutations that cause common cancers will require genomic analyses of large sets of tumor samples. Typically, the tissue material available from tumor specimens is limited, which creates a demand for accurate template amplification. We therefore evaluated whether phi29-mediated whole genome amplification introduces false positive structural mutations by massive mate-pair sequencing of a normal human genome before and after such amplification. Multiple displacement amplification led to a decrease in clone coverage and an increase by two orders of magnitude in the prevalence of inversions, but did not increase the prevalence of translocations. While multiple strand displacement amplification may find uses in translocation analyses, it is likely that alternative amplification strategies need to be developed to meet the demands of cancer genomics.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-157259 (URN)10.1371/journal.pone.0022250 (DOI)000293097300023 ()
Note
462IGPAvailable from: 2011-08-22 Created: 2011-08-22 Last updated: 2017-12-08Bibliographically approved
3. Gene rearrangements in hormone receptor negative breast cancers revealed by mate pair sequencing
Open this publication in new window or tab >>Gene rearrangements in hormone receptor negative breast cancers revealed by mate pair sequencing
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2013 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, 165Article in journal (Refereed) Published
Abstract [en]

Background: Chromosomal rearrangements in the form of deletions, insertions, inversions and translocations are frequently observed in breast cancer genomes, and a subset of these rearrangements may play a crucial role in tumorigenesis. To identify novel somatic chromosomal rearrangements, we determined the genome structures of 15 hormone-receptor negative breast tumors by long-insert mate pair massively parallel sequencing. Results: We identified and validated 40 somatic structural alterations, including the recurring fusion between genes DDX10 and SKA3 and translocations involving the EPHA5 gene. Other rearrangements were found to affect genes in pathways involved in epigenetic regulation, mitosis and signal transduction, underscoring their potential role in breast tumorigenesis. RNA interference-mediated suppression of five candidate genes (DDX10, SKA3, EPHA5, CLTC and TNIK) led to inhibition of breast cancer cell growth. Moreover, downregulation of DDX10 in breast cancer cells lead to an increased frequency of apoptotic nuclear morphology. Conclusions: Using whole genome mate pair sequencing and RNA interference assays, we have discovered a number of novel gene rearrangements in breast cancer genomes and identified DDX10, SKA3, EPHA5, CLTC and TNIK as potential cancer genes with impact on the growth and proliferation of breast cancer cells.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-182312 (URN)10.1186/1471-2164-14-165 (DOI)000316207800001 ()23496902 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2012-10-09 Created: 2012-10-09 Last updated: 2017-12-07Bibliographically approved
4. Interpreting translocations detected by paired-end sequencing of cancer samples
Open this publication in new window or tab >>Interpreting translocations detected by paired-end sequencing of cancer samples
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2012 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105Article in journal (Refereed) Submitted
National Category
Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-182309 (URN)
Available from: 2012-10-09 Created: 2012-10-09 Last updated: 2017-12-07Bibliographically approved

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