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Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Obstetrisk forskning/Höglund)
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2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. 407-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.

Place, publisher, year, edition, pages
2012. Vol. 12, p. 407-
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-186137DOI: 10.1186/1471-2407-12-407ISI: 000311048400001PubMedID: 22967087OAI: oai:DiVA.org:uu-186137DiVA, id: diva2:572694
Available from: 2012-11-28 Created: 2012-11-28 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Copy Number Analysis of Cancer
Open this publication in new window or tab >>Copy Number Analysis of Cancer
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. p. 42
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1072
Keyword
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:nbn:se:uu:diva-244361 (URN)978-91-554-9175-8 (ISBN)
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: 2018-01-11

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