Papillary and Follicular Thyroid Carcinomas Show Distinctly Different Microarray Expression Profiles and Can Be Distinguished by a Minimum of Five Genes

Aldred, Micheala A.; Huang, Ying; Liyanarachchi, Sandya; Pellegata, Natalia S.; Gimm, Oliver; Jhiang, Sissy; Davuluri, Raniana V.; Chapelle, Albert de la; Eng, Charis

doi:10.1200/jco.2004.08.127

Cited by 132 publications

(92 citation statements)

References 23 publications

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“…Decreased caveolin expression has previously been observed in Tg-A2aR mice (Goffard et al, 2004) and has also been shown to be a characteristic of thyroid follicular carcinomas (Aldred et al, 2003(Aldred et al, , 2004. The decreased expression in autonomous adenomas, which are benign, noninvading tumors, certainly shows that, as for N-cadherin overexpression, underexpression of caveolins is not sufficient to confer a malignant phenotype and is not even a marker of malignancy.…”

Section: Discussionmentioning

confidence: 86%

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Wattel¹,

Mircescu²,

Venet³

et al. 2005

Oncogene

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The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18 000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.Oncogene (2005) 24, 6902-6916.

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Section: Discussionmentioning

confidence: 86%

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Wattel¹,

Mircescu²,

Venet³

et al. 2005

Oncogene

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“…Genes regulated in a similar direction in cultured thyrocytes and autonomous adenomas, but that are regulated in the inverse way in papillary carcinomas, might reflect the differentiating action of the TSH-cAMP pathway [DIO2 (26,37), HGD (38), FHL1 (39), ITPR1 (39,40), CRABP1 (40,41), and ADM (40)], whereas common expression in the TSH-stimulated thyrocytes, autonomous adenomas, and papillary carcinomas concerns possibly proteins involved in the control or support of cell growth [EFHD2, IER2, KLF6 (10), EGR1 (10), GADD45B, and JUN]. One puzzling common property of autonomous adenomas and papillary carcinomas is the down-regulation of a number of immediate early genes [NR4A1, JUNB (10), KLF10, and ZFP36].…”

Section: Discussionmentioning

confidence: 99%

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Staveren¹,

Solís²,

Delys³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The cAMP signaling pathway regulates growth of many cell types, including somatotrophs, thyrocytes, melanocytes, ovarian follicular granulosa cells, adrenocortical cells, and keratinocytes. Mutations of partners from the cAMP signaling cascade are involved in tumor formation. Thyroid-stimulating hormone (TSH) receptor and Gs␣ activating mutations have been detected in thyroid autonomous adenomas, Gs␣ mutations in growth hormone-secreting pituitary adenomas, and PKAR1A mutations in Carney complex, a multiple neoplasia syndrome. To gain more insight into the role of cAMP signaling in tumor formation, human primary cultures of thyrocytes were treated for different times (1.5, 3, 16, 24, and 48 h) with TSH to characterize modulations in gene expression using cDNA microarrays. This kinetic study showed a clear difference in expression, early (1.5 and 3 h) and late (16 -48 h) after the onset of TSH stimulation. This result suggests a progressive sequential process leading to a change of cell program. The gene expression profile of the long-term stimulated cultures resembled the autonomous adenomas, but not papillary carcinomas. The molecular phenotype of the adenomas thus confirms the role of long-term stimulation of the TSH-cAMP cascade in the pathology. TSH induced a striking up-regulation of different negative feedback modulators of the cAMP cascade, presumably insuring the oneshot effect of the stimulus. Some were down-or nonregulated in adenomas, suggesting a loss of negative feedback control in the tumors. These results suggest that in tumorigenesis, activation of proliferation pathways may be complemented by suppression of multiple corresponding negative feedbacks, i.e., specific tumor suppressors.cyclic AMP ͉ microarrays ͉ papillary tumors ͉ thyrotropin T ight regulation of the second messenger cAMP is of crucial importance for cells because it regulates function, differentiation, and proliferation (1). In cells in which cAMP stimulates growth, activating mutations in partners of this pathway induce uncontrolled growth. In most benign thyroid autonomous adenomas, activating mutations have been found in the thyroidstimulating hormone (TSH) receptor (TSHR) (2) and, to a lesser extent, in the Gs␣ protein, an activator of the cAMP-producing adenylyl cyclase (1, 3). These mutations result in a TSHindependent growth and lead to hyperfunction (1). In addition, activating mutations of the Gs␣ protein have been detected in growth hormone-secreting pituitary adenomas (4) and inactivating mutations in the type I-␣ regulatory subunit inhibiting protein kinase A (PKAR1A) in Carney complex, a multiple neoplasia syndrome (5).Our knowledge of the genes regulated by the cAMP-protein kinase A cascade and its uncontrolled activation is still sketchy (6). To gain more insight into the cAMP-activated signal transduction cascade in tumors, human primary cultures of thyrocytes treated for different times with the TSH growth and differentiation stimulus were used as a model. Thyrocytes in primary culture are expected to be better mod...

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“…Genomic and proteomic molecular profiling is providing new insights into cancer by revealing distinctive gene expression patterns associated with a wide variety of molecular and clinical parameters (Hanash, 2004). These approaches are beginning to be applied to thyroid cancer (Huang et al, 2001;Barden et al, 2003;Aldred et al, 2004;Chevillard et al, 2004;Finley et al, 2004;Frattini et al, 2004;Hawthorn et al, 2004;Mazzanti et al, 2004;Wreesmann et al, 2004) and should yield significant improvements in thyroid cancer diagnosis, prognosis and treatment.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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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 mutationspecific 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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Papillary and Follicular Thyroid Carcinomas Show Distinctly Different Microarray Expression Profiles and Can Be Distinguished by a Minimum of Five Genes

Cited by 132 publications

References 23 publications

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

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

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