The doctoral dissertations of the former Helsinki University of Technology (TKK) and Aalto University Schools of Technology (CHEM, ELEC, ENG, SCI) published in electronic format are available in the electronic publications archive of Aalto University - Aaltodoc.
Aalto

Expression Microarray Technology as a Tool in Cancer Research

Antti Kokko

Dissertation for the degree of Doctor of Science in Technology to be presented with due permission of the Department of Chemical Technology for public examination and debate in Auditorium AS1 at Helsinki University of Technology (Espoo, Finland) on the 29th of September, 2006, at 12 noon.

Overview in PDF format (ISBN 951-22-8338-7)   [1553 KB]
Dissertation is also available in print (ISBN 951-22-8337-9)

Abstract

DNA microarray technology has in a decade been rapidly adopted by biomedical researchers and emerged as a very prominent research tool. In this study, microarray technology, together with supporting methods, was utilized in studies of human cancer. The study focused on two types of cancer, a hereditary syndrome called Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and on colorectal cancer (CRC). HLRCC is a disease caused by mutations in the Krebs cycle gene fumarase, where some of the patients develop an aggressive and early-onset renal cancer or uterine leiomyosarcoma. CRC is one of the leading causes of death in the Western world. In the first study, yeast models with fumarase mutations were subjected to microarray profiling and functional experiments to reveal changes caused by two different fumarase mutations and to find potential candidate genes for the renal cancer observed in some of the HLRCC patients. No significant differences in fumarase gene or protein expressions or in enzyme activities were observed. This indicated that modifying genes, rather than genotype-phenotype effects, play a role in the formation of the malign tumors. In the second study, Dukes' C stage colorectal tumors with good and bad prognosis were studied using microarray profiling, and a molecular signature separating these two groups with differing prognoses was identified. The study showed that gene expression profiling of surgical samples can predict the recurrence of Dukes' C patients. In the third study, serrated colorectal carcinomas, which differ morphologically from conventional colorectal carcinomas, were distinguished from each other using expression microarrays. The separation by unsupervised clustering indicated that serrated tumors differ biologically from conventional ones. Statistical analyses were used to identify key genes with differential expression between these two tumor types and the results were further validated by immunohistochemical analyses. A key gene, EPHB2, revealed by the expression data analysis of serrated CRC, was further characterized in the last two studies to find out more about the relevance of this gene to colorectal tumorigenesis. Germline mutations in EPHB2 were found in few CRC patients, but did not appear to be a major contributor in CRC susceptibility. Aberrant promoter hypermethylation and frameshift mutations in a repetitive track of the gene were, however, found to be frequent mechanisms of EPHB2 inactivation in CRC. In general, it was observed that the use of combined research methods greatly enhance the power of microarray studies, and enable focusing of the analyses. Although the technology is presently used primarily in basic research, clinical applications are foreseeable and slowly emerging.

This thesis consists of an overview and of the following 5 publications:

  1. Kokko A, Ylisaukko-oja SK, Kiuru M, Takatalo MS, Salmikangas P, Tuimala J, Arango D, Karhu A, Aaltonen LA, Jäntti J. Modeling tumor predisposing FH mutations in yeast: effects on fumarase activity, growth phenotype and gene expression profile. International Journal of Cancer. 2006; 118: 1340-1345. © 2006 by authors and © 2006 John Wiley & Sons. By permission.
  2. Arango D, Laiho P, Kokko A, Alhopuro P, Sammalkorpi H, Salovaara R, Nicorici D, Hautaniemi S, Alazzouzi H, Mecklin J-P, Järvinen H, Hemminki A, Astola J, Schwartz Jr. S, Aaltonen LA. Gene-expression profiling predicts recurrence in Dukes' C colorectal cancer. Gastroenterology. 2005; 129: 874-884. © 2005 American Gastroenterological Association (AGA) and © 2005 Elsevier Science. By permission.
  3. Laiho P, Kokko A, Vanharanta S, Salovaara R, Sammalkorpi H, Järvinen H, Mecklin J-P, Karttunen TJ, Tuppurainen K, Davalos V, Schwartz Jr. S, Arango D, Mäkinen MJ, Aaltonen LA. Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis. Oncogene. 2006 Jul 3; (Epub ahead of print). © 2006 Nature Publishing Group. By permission.
  4. Kokko A, Laiho P, Lehtonen R, Korja S, Carvajal-Carmona LG, Järvinen H, Mecklin J-P, Eng C, Schleutker J, Tomlinson IPM, Vahteristo P, Aaltonen LA. EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis. BMC Cancer. 2006; 6: 145. © 2006 by authors.
  5. Alazzouzi H, Davalos V, Kokko A, Domingo E, Woerner SM, Wilson AJ, Konrad L, Laiho P, Espín E, Armengol M, Imai K, Yamamoto H, Mariadason JM, Gebert JF, Aaltonen LA, Schwartz Jr. S, Arango D. Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. Cancer Research. 2005; 65: 10170-10173. © 2005 American Association for Cancer Research (AACR). By permission.

Keywords: DNA microarray technology, cancer, HLRCC, CRC, EPHB2

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© 2006 Helsinki University of Technology

Last update 2011-05-26