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Krzysztof Fujarewicz¹, Micha Jarzb^3,4, Markus Eszlinger⁵, Knut Krohn^5,6, Ralf Paschke⁵, Magorzata Oczko-Wojciechowska², Magorzata Wiench², Aleksandra Kukulska², Barbara Jarzb² and Andrzej Swierniak^1,2

¹ Systems Engineering Group, Institute of Automatic Control, Silesian University of Technology, 44-100 Gliwice, Poland
² Department of Nuclear Medicine and Endocrine Oncology, Institute of Oncology, Maria Skodowska-Curie Memorial Cancer Center, Gliwice Branch, Wybrzee Armii Krajowej 15, 44-100 Gliwice, Poland
³ Departments of Tumor Biology and
⁴ Clinical Oncology, Institute of Oncology, Maria Skodowska-Curie Memorial Cancer Center, Gliwice Branch, 44-100 Gliwice, Poland
⁵ III. Medical Department and
⁶ Interdisciplinary Center of Clinical Research Leipzig, University of Leipzig, 04103 Leipzig, Germany

(Requests for offprints should be addressed to B Jarzb; Email: bjarzab{at}io.gliwice.pl)

Selection of novel molecular markers is an important goal of cancer genomics studies. The aim of our analysis was to apply the multivariate bioinformatical tools to rank the genes – potential markers of papillary thyroid cancer (PTC) according to their diagnostic usefulness. We also assessed the accuracy of benign/malignant classification, based on gene expression profiling, for PTC. We analyzed a 180-array dataset (90 HG-U95A and 90 HG-U133A oligonucleotide arrays), which included a collection of 57 PTCs, 61 benign thyroid tumors, and 62 apparently normal tissues. Gene selection was carried out by the support vector machines method with bootstrapping, which allowed us 1) ranking the genes that were most important for classification quality and appeared most frequently in the classifiers (bootstrap-based feature ranking, BBFR); 2) ranking the samples, and thus detecting cases that were most difficult to classify (bootstrap-based outlier detection). The accuracy of PTC diagnosis was 98.5% for a 20-gene classifier, its 95% confidence interval (CI) was 95.9–100%, with the lower limit of CI exceeding 95% already for five genes. Only 5 of 180 samples (2.8%) were misclassified in more than 10% of bootstrap iterations. We specified 43 genes which are most suitable as molecular markers of PTC, among them some well-known PTC markers (MET, fibronectin 1, dipeptidylpeptidase 4, or adenosine A1 receptor) and potential new ones (UDP-galactose-4-epimerase, cadherin 16, gap junction protein 3, sushi, nidogen, and EGF-like domains 1, inhibitor of DNA binding 3, RUNX1, leiomodin 1, F-box protein 9, and tripartite motif-containing 58). The highest ranking gene, metallophosphoesterase domain-containing protein 2, achieved 96.7% of the maximum BBFR score.

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