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Analysis of gene expression using gene sets discriminates cancer patients with and without late radiation toxicity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
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2006 (English)In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 3, no 10, 1904-1914 p.Article in journal (Refereed) Published
Abstract [en]

Background Radiation is an effective anti-cancer therapy but leads to severe late radiation toxicity in 5%-10% of patients. Assuming that genetic susceptibility impacts this risk, we hypothesized that the cellular response of normal tissue to X-rays could discriminate patients with and without late radiation toxicity.

Methods and Findings Prostate carcinoma patients without evidence of cancer 2 y after curative radiotherapy were recruited in the study. Blood samples of 21 patients with severe late complications from radiation and 17 patients without symptoms were collected. Stimulated peripheral lymphocytes were mock-irradiated or irradiated with 2-Gy X-rays. The 24-h radiation response was analyzed by gene expression profiling and used for classification. Classification was performed either on the expression of separate genes or, to augment the classification power, on gene sets consisting of genes grouped together based on function or cellular colocalization. X- ray irradiation altered the expression of radio-responsive genes in both groups. This response was variable across individuals, and the expression of the most significant radio-responsive genes was unlinked to radiation toxicity. The classifier based on the radiation response of separate genes correctly classified 63% of the patients. The classifier based on affected gene sets improved correct classification to 86%, although on the individual level only 21/38 (55%) patients were classified with high certainty. The majority of the discriminative genes and gene sets belonged to the ubiquitin, apoptosis, and stress signaling networks. The apoptotic response appeared more pronounced in patients that did not develop toxicity. In an independent set of 12 patients, the toxicity status of eight was predicted correctly by the gene set classifier.

Conclusions Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity. Moreover, the discriminative power was enhanced by assessment of functionally or structurally related gene sets. While prediction of individual response requires improvement, this study is a step forward in predicting susceptibility to late radiation toxicity.

Place, publisher, year, edition, pages
2006. Vol. 3, no 10, 1904-1914 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94914DOI: 10.1371/journal.pmed.0030422ISI: 000241923900038PubMedID: 17076557OAI: oai:DiVA.org:uu-94914DiVA: diva2:168934
Available from: 2006-09-29 Created: 2006-09-29 Last updated: 2011-05-11Bibliographically approved
In thesis
1. Systematic Modular Approaches to Reveal DNA Damage Responses in Mammalian Cells
Open this publication in new window or tab >>Systematic Modular Approaches to Reveal DNA Damage Responses in Mammalian Cells
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer therapy operates by inflicting damage in malignant cells. The most lethal target is the genomic DNA. As a single double strand DNA break has the potential to kill the cell, mechanisms have evolved to detect and block propagation of the damage. Genes and their products function in a highly connected network-structure with ample cross-talk between different pathways. This interplay can be studied by genome-wide experiments, such as expression profiling. The aim of this thesis is to study the cellular effects of DNA damaging agents.

A theoretical framework is explored to improve understanding of expression profiling results. To analyse large datasets, computational methods were developed to model the data. Further, the response to DNA damage was investigated in different cellular systems. As late radiation toxicity is a severe limitation of radiotherapy of cancer patients, patients were enrolled in a study to search for a molecular signature to identify high-risk patients. Ex vivo irradiation of lymphocytes revealed a signature of functionally related gene sets that were capable to separate patients with regard to toxicity status.

The gene set analysis was also applied to a dataset where mouse embryonic stem cells had been exposed to various doses of cisplatin. At several time-points after administration of the drug, expression profiles were determined. In addition to the expected increase of genes related to apoptosis and cell cycle progression, damaged cells also seemed to have embarked upon a p53-dependent differentiation programme. Finally, in a study of cardiac rodent cells, the genotoxic treatment with irradiation was compared to the mechanical stress induced in heart tissue.

In conclusion, this thesis presents evidence for the advantage of using functionally related sets of genes in analysis and interpretation of genome-wide experiments. This strategy may improve clinical understanding of the effects of DNA damaging agents used for cancer therapeutics.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 70 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 176
Molecular biology, gene expression profiling, DNA damage, network, cancer, ionizing radiation, cisplatin, Molekylärbiologi
urn:nbn:se:uu:diva-7163 (URN)91-554-6667-2 (ISBN)
Public defence
2006-10-21, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 09:15
Available from: 2006-09-29 Created: 2006-09-29Bibliographically approved

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