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Genomic and genetic alterations in endometrial adenocarcinoma
University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
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.
Keyword [en]
Endometrial cancer, Genetic background, BDII rat model, SKY, Chromosomal abreations, Gene expression
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
URN: urn:nbn:se:his:diva-7421Libris ID: 14214932ISBN: 978-91-7668-913-4 OAI: oai:DiVA.org:his-7421DiVA: diva2:611675
Public defence
2013-03-01, Insikten, Högskolan i Skövde, Skövde, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2013-03-18 Created: 2013-03-18 Last updated: 2014-03-27Bibliographically 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, Vol. 11, 20- p.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
Keyword
SKY, BDII rat, endometrial carcinoma
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-5536 (URN)10.1186/1475-2867-11-20 (DOI)000293340700001 ()2-s2.0-79959571469 (Scopus ID)
Available from: 2012-03-19 Created: 2012-03-01 Last updated: 2013-03-18Bibliographically 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, 438-446 p.Article 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
Wiley-Blackwell, 2012
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-5665 (URN)10.1002/gcc.21929 (DOI)000301118100003 ()
Available from: 2012-04-02 Created: 2012-04-02 Last updated: 2013-03-18Bibliographically 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, 46- p.Article 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.

Place, publisher, year, edition, pages
BioMed Central, 2010
Keyword
Gpx3, endometrial cancer, methylation, real time PCR, FIGO grades
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-4708 (URN)10.1186/1475-2867-10-46 (DOI)000285883400001 ()2-s2.0-78549258157 (Scopus ID)
Available from: 2011-02-02 Created: 2011-02-02 Last updated: 2013-04-09Bibliographically 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
2013 (English)In: Cancer Cell International, ISSN 1475-2867, Vol. 13, no 1, 43Article in journal (Refereed) Published
Abstract [en]

Endometrial adenocarcinoma is the most frequently diagnosed cancer of the female genital tract in the western world. Studies of complex diseases can be difficult to perform on human tumor samples due to the high genetic heterogeneity in human. The use of rat models is preferable since rat has similarities in pathogenesis and histopathological properties to that of human.

A genomic region including the highly conserved Phf5a gene associated to development of EAC has previously been identified in an association study. PHF5A has been suggested to acts as a transcription factor or cofactor in the up regulation of expression of Gja1 gene in the presence of estrogen. It has earlier been shown that the Phf5a gene is down regulated in rat EAC derived cell lines by means of expression microarrays.

We analyzed the expression of Phf5a and Gja1 by qPCR, and potential relations between the two genes in EAC tumors and non-malignant cell lines derived from the BDII rat model. In addition, the expression pattern of these genes was compared in rat and human EAC tumor samples.

Changes in expression for Phf5a/PHF5A were found in tumors from both rat and human even though the observed pattern was not completely consistent between the two species. By separating rat EAC cell lines according to the genetic background, a significant lower expression of Phf5a in one of the two cross backgrounds was revealed, but not for the other. In contrast to other studies, Phf5a/PHF5A regulation of Gja1/GJA1 was not revealed in this study.

Place, publisher, year, edition, pages
BioMed Central, 2013
Keyword
BDII, Endometrial cancer, Genetic background, Phf5a, Gja1
National Category
Medical and Health Sciences
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-7420 (URN)10.1186/1475-2867-13-43 (DOI)000319389700001 ()23675859 (PubMedID)2-s2.0-84878075429 (Scopus ID)
Available from: 2013-03-18 Created: 2013-03-18 Last updated: 2015-08-13Bibliographically approved

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