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Copy Number Analysis of Cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Anders Isaksson)ORCID iD: 0000-0003-3403-0083
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

By accurately describing cancer genomes, we may link genomic mutations to phenotypic effects and eventually treat cancer patients based on the molecular cause of their disease, rather than generalizing treatment based on cell morphology or tissue of origin.

Alteration of DNA copy number is a driving mutational process in the formation and progression of cancer. Deletions and amplifications of specific chromosomal regions are important for cancer diagnosis and prognosis, and copy number analysis has become standard practice for many clinicians and researchers. In this thesis we describe the development of two computational methods, TAPS and Patchwork, for analysis of genome-wide absolute allele-specific copy number per cell in tumour samples. TAPS is used with SNP microarray data and Patchwork with whole genome sequencing data. Both are suitable for unknown average ploidy of the tumour cells, are robust to admixture of genetically normal cells, and may be used to detect genetic heterogeneity in the tumour cell population. We also present two studies where TAPS was used to find copy number alterations associated with risk of recurrence after surgery, in ovarian cancer and colon cancer. We discuss the potential of such prognostic markers and the use of allele-specific copy number analysis in research and diagnostics.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 42 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1072
Keyword [en]
chromosomes, oncology, bioinformatics
National Category
Bioinformatics (Computational Biology) Genetics Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Bioinformatics; Oncology; Clinical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-244361ISBN: 978-91-554-9175-8 (print)OAI: oai:DiVA.org:uu-244361DiVA: diva2:791215
Public defence
2015-04-17, BMC E10:1307-1309, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2015-03-26 Created: 2015-02-16 Last updated: 2015-04-17
List of papers
1. Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity
Open this publication in new window or tab >>Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity
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2011 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, no 10, R108- p.Article in journal (Refereed) Published
Abstract [en]

We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors.

National Category
Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-164141 (URN)10.1186/gb-2011-12-10-r108 (DOI)000301176900011 ()22023820 (PubMedID)
Available from: 2011-12-16 Created: 2011-12-16 Last updated: 2017-12-08Bibliographically approved
2. Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease
Open this publication in new window or tab >>Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease
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2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, 407- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Ovarian cancer is a heterogeneous disease and prognosis for apparently similar cases of ovarian cancer varies. Recurrence of the disease in early stage (FIGO-stages I-II) serous ovarian cancer results in survival that is comparable to those with recurrent advanced-stage disease. The aim of this study was to investigate if there are specific genomic aberrations that may explain recurrence and clinical outcome.

METHODS:

Fifty-one women with early stage serous ovarian cancer were included in the study. DNA was extracted from formalin fixed samples containing tumor cells from ovarian tumors. Tumor samples from thirty-seven patients were analysed for allele-specific copy numbers using OncoScan single nucleotide polymorphism arrays from Affymetrix and the bioinformatic tool Tumor Aberration Prediction Suite. Genomic gains, losses, and loss-of-heterozygosity that associated with recurrent disease were identified.

RESULTS:

The most significant differences (p < 0.01) in Loss-of-heterozygosity (LOH) were identified in two relatively small regions of chromosome 19; 8.0-8,8 Mbp (19 genes) and 51.5-53.0 Mbp (37 genes). Thus, 56 genes on chromosome 19 were potential candidate genes associated with clinical outcome. LOH at 19q (51-56 Mbp) was associated with shorter disease-free survival and was an independent prognostic factor for survival in a multivariate Cox regression analysis. In particular LOH on chromosome 19q (51-56 Mbp) was significantly (p < 0.01) associated with loss of TP53 function.

CONCLUSIONS:

The results of our study indicate that presence of two aberrations in TP53 on 17p and LOH on 19q in early stage serous ovarian cancer is associated with recurrent disease. Further studies related to the findings of chromosomes 17 and 19 are needed to elucidate the molecular mechanism behind the recurring genomic aberrations and the poor clinical outcome.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-186137 (URN)10.1186/1471-2407-12-407 (DOI)000311048400001 ()22967087 (PubMedID)
Available from: 2012-11-28 Created: 2012-11-28 Last updated: 2017-12-07Bibliographically approved
3. Patchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue
Open this publication in new window or tab >>Patchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue
2013 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 3, R24- p.Article in journal (Refereed) Published
Abstract [en]

Whole-genome sequencing of tumor tissue has the potential to provide comprehensive characterization of genomic alterations in tumor samples. We present Patchwork, a new bioinformatic tool for allele-specific copy number analysis using whole-genome sequencing data. Patchwork can be used to determine the copy number of homologous sequences throughout the genome, even in aneuploid samples with moderate sequence coverage and tumor cell content. No prior knowledge of average ploidy or tumor cell content is required. Patchwork is freely available as an R package, installable via R-Forge (http://patchwork.r-forge.r-project.org/).

Keyword
Cancer, allele-specific copy number analysis, whole-genome sequencing, aneuploidy, tumor heterogeneity, chromothripsis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-215306 (URN)10.1186/gb-2013-14-3-r24 (DOI)000328193700004 ()
Available from: 2014-01-13 Created: 2014-01-13 Last updated: 2017-12-06Bibliographically approved
4. 1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer
Open this publication in new window or tab >>1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer
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2014 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, 872- p.Article in journal (Refereed) Published
Abstract [en]

Background: The clinical behaviour of colon cancer is heterogeneous. Five-year overall survival is 50-65% with all stages included. Recurring somatic chromosomal alterations have been identified and some have shown potential as markers for dissemination of the tumour, which is responsible for most colon cancer deaths. We investigated 115 selected stage II-IV primary colon cancers for associations between chromosomal alterations and tumour dissemination. Methods: Follow-up was at least 5 years for stage II-III patients without distant recurrence. Affymetrix SNP 6.0 microarrays and allele-specific copy number analysis were used to identify chromosomal alterations. Fisher's exact test was used to associate alterations with tumour dissemination, detected at diagnosis (stage IV) or later as recurrent disease (stage II-III). Results: Loss of 1p36.11-21 was associated with tumour dissemination in microsatellite stable tumours of stage II-IV (odds ratio = 5.5). It was enriched to a similar extent in tumours with distant recurrence within stage II and stage III subgroups, and may therefore be used as a prognostic marker at diagnosis. Loss of 1p36.11-21 relative to average copy number of the genome showed similar prognostic value compared to absolute loss of copies. Therefore, the use of relative loss as a prognostic marker would benefit more patients by applying also to hyperploid cancer genomes. The association with tumour dissemination was supported by independent data from the The Cancer Genome Atlas. Conclusion: Deletions on 1p36 may be used to guide adjuvant treatment decisions in microsatellite stable colon cancer of stages II and III.

Keyword
Colon cancer, Prognostic marker, Allele-specific copy number analysis, Genome duplication, 1p36, Metastasis, Tumour dissemination
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-240088 (URN)10.1186/1471-2407-14-872 (DOI)000345660000001 ()25420937 (PubMedID)
Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2017-12-05Bibliographically approved

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