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Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy.
KTH, School of Biotechnology (BIO), Gene Technology.
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2005 (English)In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Surgery, Vol. 138, no 6, 1087-1094 p.Article in journal (Refereed) Published
Abstract [en]

Background. Distinguishing between adrenocortical adenomas and carcinomas is often difficult. Our aim was to investigate the differences in transcriptional profiles between benign and malignant adrenocortical neoplasms using complementary DNA microarray techniques.

Methods. We studied 7 patients with adrenocortical carcinomas and 13 with adenomas. Histopathology was reviewed in all patients, clinical follow-up was at least 1 year. Hybridizations were Performed in duplicate against RNA reference. Expression levels were analyzed in the R environment for statistical computing with the use of aroma, limma, statistics, and class packages.

Results. Transcriptional profiles were homogeneous among adenomas, while carcinomas were much more heterogeneous. Hierarchical clustering and self-organizing maps could separate clearly carcinomas from adenomas. Among genes that were most significantly upregulated in carcinomas were 2 ubiquilin-related genes (USP4 and UFD1L) and several insulinlike growth factor-related genes (IGF2, IGF2R, IGFBP3 and IGFBP6). Among genes that were most significantly downregulated in carcinomas were a cylokine gene (CXCL10), several genes related to cell metabolism (RARRES2, ALDH1A1, CYBRD1 and GSTA4), and the cadherin 2 gene (CDH2).

Conclusions. Through the use of cDNA arrays, adrenocortical adenomas and carcinomas appear to be clearly distinguishable on the basis of their specific molecular signature. The biologic importance of the up- and downregulated genes is yet to be determined.

Place, publisher, year, edition, pages
2005. Vol. 138, no 6, 1087-1094 p.
Keyword [en]
factor-binding protein-3, cancer-risk, tumors, gene, carcinoma, identification, frequent, markers, locus
National Category
Industrial Biotechnology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-6654DOI: 10.1016/j.surg.2005.09.031ISI: 000234319000032Scopus ID: 2-s2.0-29144437760OAI: oai:DiVA.org:kth-6654DiVA: diva2:11424
Note
QC 20100907Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-07Bibliographically 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.
Keyword
adrenocortical tumour, apoptosis, cancer, classification, gene expression, microarray, p53, RNA amplification
National Category
Cell and Molecular Biology
Identifiers
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
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Supervisors
Note
QC 20100907Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-07Bibliographically approved

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