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Transcriptional profiling enables molecular classification of adrenocortical tumours
KTH, School of Biotechnology (BIO), Gene Technology.
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2009 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 161, no 1, 141-152 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Tumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5-2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities. Methods: Microarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis. Results: Unsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples. Conclusions: Adrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.

Place, publisher, year, edition, pages
2009. Vol. 161, no 1, 141-152 p.
Keyword [en]
ubiquitin-specific protease, gene-expression, carcinoma, cancer, malignancy, unp, enzyme, tumorigenesis, protooncogene, microarrays
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:kth:diva-6655DOI: 10.1530/EJE-09-0068ISI: 000272934700018PubMedID: 19411298ScopusID: 2-s2.0-67650736272OAI: diva2:11425
Swedish Research Council
QC 20100907 Uppdaterad från manuskript till artikel (20100907).Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2011-04-15Bibliographically approved
In thesis
1. Microarray Based Gene Expression Analysis in Cancer Research
Open this publication in new window or tab >>Microarray Based Gene Expression Analysis in Cancer Research
2006 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Biotechnological inventions during the 20th century have resulted in a wide range of approaches for explorations in the functional genomics field. Microarray technology is one of the recent advances which have provided us with snapshots of which genes are expressed in cells of various tissues and diseases. Methods to obtain reliable microarray data are continuously being developed and improved to meet the demands of biological researchers.

In this thesis microarrays have been used to investigate gene expression patterns in cancer research. Four studies in three different areas were carried out covering adrenocortical tumors, p53 target genes and a comparison of RNA amplification methods.

Adrenocortical tumours are among the most common tumours with an incidence of 7-9%. Malignancy of these tumors is rare. Distinction between malignant and benign tumours is often difficult to establish which makes an improvement of diagnostic approaches important. To elucidate biological processes in adrenocortical tumour development and to examine if there is a molecular signature associated with malignancy, microarray analysis was performed on 29 adrenocortical tumors and four normal specimens. It was possible to classify malignant and benign samples based on the entire expression profile. A number of potential biomarkers was identified which will be further evaluated.

P53 is a gene which is mutated in 50% of all cancers. Functional p53 is a transcription factor which is activated upon cellular stress and DNA damage. Target genes are mainly involved in cell cycle arrest and apoptosis. In solid tumors cells are stressed by hypoxia. To examine which target genes p53 activate under hypoxic conditions a microarray study of the cell lines HCT116p53+/+ and HCT116p53-/- was performed. A set of novel potential p53 target genes was identified while many known target genes were found to be not transcriptionally activated during hypoxia. Follow up which was focused on how p53 affected hypoxia induced apoptosis showed that the death receptor Fas was critical.

When small amounts of tissue are available, amplification of the transcript population is necessary for microarray analysis. A new strategy for amplification based on PCR was evaluated and compared to a commercial in vitro transcription protocol. Both protocols produced reliable results. Advantages with the PCR based method are a lower cost and a high flexibility due to compatibility with both sense and antisense strand microarrays.

Keywords: adrenocortical tumour, apoptosis, cancer, classification, gene expression, microarray, p53, RNA amplification

Place, publisher, year, edition, pages
Stockholm: KTH, 2006. 76 p.
adrenocortical tumour, apoptosis, cancer, classification, gene expression, microarray, p53, RNA amplification
National Category
Cell and Molecular Biology
urn:nbn:se:kth:diva-4244 (URN)91-7178-542-6 (ISBN)978-91-7178-542-8 (ISBN)
Public defence
2006-12-22, FD5, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
QC 20100907Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-07Bibliographically approved

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