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Genomic and genetic alterations in endometrial adenocarcinoma
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The most frequently diagnosed cancer of the female genital tract is cancer of the endometrium (endometrial cancer), ranking fourth among the invasive tumors that affect women in Europe and North America. As most other cancer types, endometrial cancer is a complex genetic disease influenced by both genetic and environmental factors.

The human population is genetically heterogeneous and studies of complex diseases in human are proven to be difficult. By using a model system such as the BDII rat, some of the obstacles related to the study of complex diseases can be avoided. The BDII rat strain is prone to spontaneously develop endometrial adenocarcinoma (EAC) and more than 90% of the virgin females develop EAC during their lifetime. Development of EAC tumors in BDII rats is comparable in pathogenesis and histopathological properties to that of human.

The aims of this thesis were i/ to characterize EAC in the BDII rat experimental model system by analyzing structural and numerical chromosome aberrations, ii/ to evaluate the importance of the genetic set-up in EAC development, and iii/ to determine the impact of genomic and genetic alterations on the functionality of candidate genes in rat EAC and in human endometrial tumors of different FIGO grades.

Non-random numerical and structural aberrations that could contribute to tumor formation were identified, and evidence that the genetic background had a significant influence on the genome make-up of tumor cells was provided. Certain genes (Gpx3/GPX3, Met/MET, Phf5a/PHF5A, and Gja1/GJA1) were selected for further analysis and aberrant expression of some of them were found in both rat and human EACs. By separating EAC cell lines according to the genetic cross background, for two of the genes (Phf5 and Met), we showed that the expression pattern differed significantly between different cross backgrounds, which clearly pinpoint the importance of using animal models as a complement to clinical studies in identification of cancer-related genes.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2013.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 81
Keywords [en]
Endometrial cancer, Genetic background, BDII rat model, SKY, Chromosomal abreations, Gene expression
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-26881ISBN: 978-91-7668-913-4 (print)OAI: oai:DiVA.org:oru-26881DiVA, id: diva2:588789
Public defence
2013-03-01, Insikten, Högskolan i Skövde, Skövde, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2013-01-16 Created: 2013-01-16 Last updated: 2017-10-17Bibliographically approved
List of papers
1. SKY analysis revealed recurrent numerical and structural chromosome changes in BDII rat endometrial carcinomas
Open this publication in new window or tab >>SKY analysis revealed recurrent numerical and structural chromosome changes in BDII rat endometrial carcinomas
2011 (English)In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 11, p. 20-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Genomic alterations are common features of cancer cells, and some of these changes are proven to be neoplastic-specific. Such alterations may serve as valuable tools for diagnosis and classification of tumors, prediction of clinical outcome, disease monitoring, and choice of therapy as well as for providing clues to the location of crucial cancer-related genes.Endometrial carcinoma (EC) is the most frequently diagnosed malignancy of the female genital tract, ranking fourth among all invasive tumors affecting women. Cytogenetic studies of human ECs have not produced very conclusive data, since many of these studies are based on karyotyping of limited number of cases and no really specific karyotypic changes have yet been identified. As the majority of the genes are conserved among mammals, the use of inbred animal model systems may serve as a tool for identification of underlying genes and pathways involved in tumorigenesis in humans. In the present work we used spectral karyotyping (SKY) to identify cancer-related aberrations in a well-characterized experimental model for spontaneous endometrial carcinoma in the BDII rat tumor model.

RESULTS: Analysis of 21 experimental ECs revealed specific nonrandom numerical and structural chromosomal changes. The most recurrent numerical alterations were gains in rat chromosome 4 (RNO4) and losses in RNO15. The most commonly structural changes were mainly in form of chromosomal translocations and were detected in RNO3, RNO6, RNO10, RNO11, RNO12, and RNO20. Unbalanced chromosomal translocations involving RNO3p was the most commonly observed structural changes in this material followed by RNO11p and RNO10 translocations.

CONCLUSION: The non-random nature of these events, as documented by their high frequencies of incidence, is suggesting for dynamic selection of these changes during experimental EC tumorigenesis and therefore for their potential contribution into development of this malignancy. Comparative molecular analysis of the identified genetic changes in this tumor model with those reported in the human ECs may provide new insights into underlying genetic changes involved in EC development and tumorigenesis.

Place, publisher, year, edition, pages
BioMed Central, 2011
Keywords
SKY; BDII rat; endometrial carcinoma
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-27559 (URN)10.1186/1475-2867-11-20 (DOI)000293340700001 ()21708004 (PubMedID)2-s2.0-79959571469 (Scopus ID)
Note

Funding Agencies:

Royal Physiographic Society in Lund (Nilsson-Ehle Foundation)  

Royal Society of Arts and Sciences in Gothenburg 

Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2018-03-02Bibliographically approved
2. The impact of the genetic background on the genome make-up of tumor cells
Open this publication in new window or tab >>The impact of the genetic background on the genome make-up of tumor cells
2012 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 51, no 5, p. 438-446Article in journal (Refereed) Published
Abstract [en]

Endometrial adenocarcinoma (EAC) is the most common form of malignancy in the female genital tract, ranking as the fourth leading form of invasive tumors that affect women. The BDII inbred rat strain has been used as a powerful tumor model in studies of the genetic background of EAC. Females from the BDII strain are prone to develop tumors with an incidence of more than 90%. Development of EAC in BDII female rats has similarities in pathogenesis, histopathological, and molecular properties to that of human, and thus represents a unique model for analysis of EAC tumorigenesis and for comparative studies in human EACs. In a previous study, a set of rat EAC cell lines derived from tumors developed in female crossprogenies between BDII and nonsusceptible rat strains were analyzed by spectral karyotyping (SKY). Here we present an analysis with specific focus on the impact of different genetic backgrounds on the rate and occurrence of genetic aberrations in experimental tumors using data presented in the previous report. We could reveal that the ploidy state, and the abundance and type of structural as well as numerical change differed between the two genetic setups. We have also identified chromosomes harboring aberrations independent of genetic input from the nonsusceptible strains, which provide valuable information for the identification of the genes involved in the development of EAC in the BDII model as well as in human endometrial tumors. (C) 2012 Wiley Periodicals, Inc.

Place, publisher, year, edition, pages
Malden, USA: Wiley-Blackwell, 2012
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-22309 (URN)10.1002/gcc.21929 (DOI)000301118100003 ()22250046 (PubMedID)2-s2.0-84857997916 (Scopus ID)
Note

Funding Agencies:

Royal Physiographic Society in Lund (Nilsson-Ehle Foundation)

Stiftelsen Wilhelm och Martina Lundgrens Vetenskapsfond 

Royal Society of Arts and Sciences in Gothenburg 

Erik Philip-Sorensen Foundation 

Available from: 2012-04-02 Created: 2012-04-02 Last updated: 2017-12-07Bibliographically approved
3. Loss of glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma
Open this publication in new window or tab >>Loss of glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma
Show others...
2010 (English)In: Cancer cell international, ISSN 1475-2867, Vol. 10, article id 46Article in journal (Refereed) Published
Abstract [en]

Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-27561 (URN)10.1186/1475-2867-10-46 (DOI)000285883400001 ()21106063 (PubMedID)
Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2018-03-02Bibliographically approved
4. Expression patterns of Phf5a/PHF5A and Gja1/GJA1 in rat and human endometrial cancer
Open this publication in new window or tab >>Expression patterns of Phf5a/PHF5A and Gja1/GJA1 in rat and human endometrial cancer
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-27563 (URN)
Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2017-10-17Bibliographically approved

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