Molecular classification of papillary thyroid carcinoma:: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis
Molecular classification of papillary thyroid carcinoma:: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis
复制标题
DOI：
10.1038/sj.onc.1208822
复制
发表时间：
2005-10-06
期刊：
影响因子：
8
通讯作者：
Nikiforov, YE
中科院分区：
文献类型：
--
作者：
Giordano, TJ;Kuick, R;Nikiforov, YE
甲状腺癌构成了重大的临床挑战，我们对其发病机理的理解是不完整的。为了深入了解乳头状甲状腺癌的发病机理，使用DNA微阵列产生了四个正常甲状腺和51个乳头状癌（PC）的转录谱。肿瘤的共同激活突变是基因分型的：BRAF V600E点突变，RET/PTC1和3重排和KRAS，HRAS和NRA的点突变。基于整个表达数据集的主成分分析将PC分为三组，这些组被发现反映了肿瘤形态和突变状态。通过将表达谱与突变状态相结合，我们定义了BRAF，RET/PTC1和RAS突变组的不同表达谱。使用少量基因，一个简单的分类器能够正确对所有40个肿瘤的突变状态进行分类。分类器预测一个没有可检测突变的肿瘤具有RET/PTC重排，并显示通过荧光原位杂交分析包含一个肿瘤。在突变特异性表达特征的特征中，其差异表达是突变的直接结果，以及参与多种生物学过程的基因，包括免疫反应和信号转导。一种突变特异性差异表达的基因TPO的表达在蛋白质水平上使用免疫组织化学和包含独立肿瘤集的组织阵列进行了验证。结果表明，突变状态是这些肿瘤中基因表达变异的主要决定因素，这一发现可能具有临床和诊断意义，并预测旨在防止这些突变后果的疗法的成功。
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/PTC1 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.