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Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis

Oncogene volume 24, pages 6646–6656 (2005)Cite this article

Abstract

Thyroid cancer poses a significant clinical challenge, and our understanding of its pathogenesis is incomplete. To gain insight into the pathogenesis of papillary thyroid carcinoma, transcriptional profiles of four normal thyroids and 51 papillary carcinomas (PCs) were generated using DNA microarrays. The tumors were genotyped for their common activating mutations: BRAF V600E point mutation, RET/PTC1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS. Principal component analysis based on the entire expression data set separated the PCs into three groups that were found to reflect tumor morphology and mutational status. By combining expression profiles with mutational status, we defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups. Using small numbers of genes, a simple classifier was able to classify correctly the mutational status of all 40 tumors with known mutations. One tumor without a detectable mutation was predicted by the classifier to have a RET/PTC rearrangement and was shown to contain one by fluorescence in situ hybridization analysis. Among the mutation-specific expression signatures were genes whose differential expression was a direct consequence of the mutation, as well as genes involved in a variety of biological processes including immune response and signal transduction. Expression of one mutation-specific differentially expressed gene, TPO, was validated at the protein level using immunohistochemistry and tissue arrays containing an independent set of tumors. The results demonstrate that mutational status is the primary determinant of gene expression variation within these tumors, a finding that may have clinical and diagnostic significance and predicts success for therapies designed to prevent the consequences of these mutations.

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Acknowledgements

This work was supported in part by funds from the Marilynn Collins Thyroid Cancer Fund and the Millie Schembechler Endocrine Cancer Program of the University of Michigan Comprehensive Cancer, the Michigan NIDDK Biotechnology Center (NIH DK58771), the Michigan Diabetes Research and Training Center (NIH DK20572) and the National Institutes of Health (NIH CA88041 and NIH 5 P30 CA46592), and also supported by infrastructure provided by the NCI Director's Challenge Program at the University of Michigan (NIH CA84952). We thank the current and former technicians of the Tissue Procurement Service of the University of Michigan Comprehensive Cancer Center, specifically Donna Renner-Chuey, Doug Selby, John Weeks, Enola Cushenberry and Tony Iacco. We thank Barbara Lamb for excellent technical assistance with the DNA microarray analysis. We also thank Mary Hong for excellent organizational assistance and Georgann McCain for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Pathology, UH 2G332/0054, University of Michigan Medical School and Comprehensive Cancer Center, University of Michigan, Ann Arbor, 48109-0054, MI, USA

    Thomas J Giordano, Dafydd G Thomas, Michelle Vinco, Donita Sanders & Michael Roh

  2. Department of Pediatrics, University of Michigan Medical School, University of Michigan, Ann Arbor, 48109-0054, MI, USA

    Rork Kuick, David E Misek & Samir Hanash

  3. Department of Internal Medicine, University of Michigan Medical School, University of Michigan, Ann Arbor, 48109-0054, MI, USA

    Dafydd G Thomas & Ronald J Koenig

  4. Department of Pathology, University of Cincinnati Medical School, Cincinnati, OH, USA

    Zhaowen Zhu, Raffaele Ciampi & Yuri E Nikiforov

  5. Department of Statistics, University of Michigan Medical School, University of Michigan, Ann Arbor, 48109-0054, MI, USA

    Kerby Shedden

  6. Department of Surgery, University of Michigan Medical School, University of Michigan, Ann Arbor, 48109-0054, MI, USA

    Paul Gauger, Gerard Doherty & Norman W Thompson

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  1. Thomas J Giordano
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Correspondence to Thomas J Giordano.

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Giordano, T., Kuick, R., Thomas, D. et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene 24, 6646–6656 (2005). https://doi.org/10.1038/sj.onc.1208822

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