Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis.
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.
Giordano
Thomas J
TJ
Department of Pathology, UH 2G332/0054, University of Michigan Medical School, Ann Arbor, 48109-0054, USA. Giordano@umich.edu
Kuick
Rork
R
Thomas
Dafydd G
DG
Misek
David E
DE
Vinco
Michelle
M
Sanders
Donita
D
Zhu
Zhaowen
Z
Ciampi
Raffaele
R
Roh
Michael
M
Shedden
Kerby
K
Gauger
Paul
P
Doherty
Gerard
G
Thompson
Norman W
NW
Hanash
Samir
S
Koenig
Ronald J
RJ
Nikiforov
Yuri E
YE
D001483:Base Sequence; D017931:DNA Primers; D020869:Gene Expression Profiling; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007453:Iodide Peroxidase / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled; D013964:Thyroid Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic; D000098706:Taste Receptors, Type 2
D017931:DNA Primers; D015513:Oncogene Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2; D007453:Iodide Peroxidase; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf