Aneuploidy and <i>RAS</i> mutations are mutually exclusive events in the development of well‐differentiated thyroid follicular tumours

Banito, Ana; Pinto, António E.; Espadinha, Carla; Marques, Ana Rita; Leite, Valeriano

doi:10.1111/j.1365-2265.2007.02949.x

Cited by 16 publications

(18 citation statements)

References 43 publications

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“…These observations indicate that PDTC may have abnormalities in MSAC or in the attachment of kinetochores, which may compromise mitotic fidelity and contribute to chromosomal instability. Accordingly, we observed earlier (Banito et al, 2007) that four out of the five PDTC analysed in this study were aneuploid.…”

Section: Discussionsupporting

confidence: 67%

Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

et al. 2009

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BACKGROUND: Poorly differentiated thyroid carcinomas (PDTC) represent a heterogeneous, aggressive entity, presenting features that suggest a progression from well-differentiated carcinomas. To elucidate the mechanisms underlying such progression and identify novel therapeutic targets, we assessed the genome-wide expression in normal and tumour thyroid tissues. METHODS: Microarray analyses of 24 thyroid carcinomas -7 classic papillary, 8 follicular variants of papillary (fvPTC), 4 follicular (FTC) and 5 PDTC -were performed and correlated with RAS, BRAF, RET/PTC and PAX8-PPARG alterations. Selected genes were validated by quantitative RT -PCR in an independent set of 28 thyroid tumours. RESULTS: Unsupervised analyses showed that gene expression similarity was higher between PDTC and fvPTC, particularly for tumours harbouring RAS mutations. Poorly differentiated thyroid carcinomas presented molecular signatures related to cell proliferation, poor prognosis, spindle assembly checkpoint and cell adhesion. Compared with normal tissues, PTC had 307 out of 494 (60%) genes over-expressed, FTC had 137 out of 171 (80%) genes under-expressed, whereas PDTC had 92 out of 107 (86%) genes under-expressed, suggesting that gene downregulation is involved in tumour dedifferentiation. Significant UHRF1 and ITIH5 deregulated gene expression in PDTC, relatively to normal tissues, was confirmed by quantitative RT -PCR. CONCLUSION: Our findings suggest that fvPTC are possible precursors of PDTC. Furthermore, UHRF1 and ITIH5 have a potential therapeutic/prognostic value for aggressive thyroid tumours.

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Section: Discussionsupporting

confidence: 67%

Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

et al. 2009

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“…7 However, there are conflicting data on the prognostic impact of PPFP in FTC, with our group 7 and several others, [8][9][10][11][12][13] indicating that PPFP is associated with a less aggressive phenotype, while others 14-16 observe a more aggressive phenotype in their patient population. We therefore hypothesize that PPFP acts not as a pure oncogene but as a modulator of oncogenesis, affecting tumor progression in potentially complex ways that ultimately lead to a more favorable outcome.…”

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confidence: 86%

The Putative PAX8/PPAR Fusion Oncoprotein Exhibits Partial Tumor Suppressor Activity through Up-Regulation of Micro-RNA-122 and Dominant-Negative PPAR Activity

et al. 2011

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IntroductionFollicular thyroid carcinoma (FTC) accounts for up to 20% of all thyroid cancers but is responsible for up to 40% of the deaths associated with this disease.1 In contrast to the wealth of mechanistic information available regarding the pathogenesis of papillary thyroid carcinoma (PTC), the triggering mechanisms of FTC development have remained obscure. PAX8/PPARγ rearrangements, which express the PAX8/PPARγ fusion protein (PPFP), are found in about 36% of FTC.2 Because such rearrangements are associated with oncogenesis in other systems, 3 PPFP has been implicated in the pathogenesis of FTC. Furthermore, our group and others have confirmed that PPFP acts as an oncogene in vitro, with increased rates of cell growth and attachmentindependent growth and decreased rates of apoptosis of several cell lines in vitro. 4,5 However, PPFP fails to transform normal thyrocytes in a transgenic animal, 6 suggesting that other oncogenic events are required to elicit its oncogenic actions. Consequently, the precise role of PPFP in the pathogenesis of FTC remains uncertain.We have demonstrated that the presence of PPFP in human tumors is associated with reduced CD-31 staining, suggesting decreased neovascularization.2 This finding is congruent with our earlier study of a cohort of 54 FTC patients, in which the 31 tumors that expressed PPFP exhibited favorable prognostic indicators, including better tumor Submitted 27- Dec-2010; revised 22-Feb-2011; accepted 27-Feb-2011 AbstractIn vitro studies have demonstrated that the PAX8/PPARγ fusion protein (PPFP), which occurs frequently in follicular thyroid carcinomas (FTC), exhibits oncogenic activity. However, paradoxically, a meta-analysis of extant tumor outcome studies indicates that 68% of FTC-expressing PPFP are minimally invasive compared to only 32% of those lacking PPFP (χ 2 = 6.86, P = 0.008), suggesting that PPFP favorably impacts FTC outcomes. In studies designed to distinguish benign thyroid neoplasms from thyroid carcinomas, the previously identified tumor suppressor miR-122, a major liver micro-RNA (miR) that is decreased in hepatocellular carcinoma, was increased 8.9-fold (P < 0.05) in all FTC versus normal, 9.2-fold in FTC versus FA (P < 0.05), and 16.8-fold (P < 0.001) in FTC + PPFP versus FTC -PPFP. Constitutive expression of PPFP in the FTC-derived cell line WRO (WRO-PPFP) caused a 5-fold increase of miR-122 expression (P < 0.05) and a striking 5.1-fold reduction (P < 0.0001) in tumor progression compared to WRO-vector cells in a mouse xenograft model. Constitutive expression of either miR-122 or a dominant-negative PPARγ mutant in WRO cells was less effective than PPFP at inhibiting xenograft tumor progression (1.8-fold [P < 0.001] and 1.7-fold [P < 0.03], respectively). PPFP-induced up-regulation of miR-122 expression was independent of its known dominant-negative PPARγ activity. Up-regulation of miR-122 negatively regulates ADAM-17, a known downstream target, in thyroid cells, suggesting an antiangiogenic mechanism in thyroid carcinoma. This latter ...

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Section: Diagnostic Utility Of Ras Mutationmentioning

confidence: 99%

“…These 21-kDa membrane- [4,9,12,15,16]. Thyroid neoplasms are unique in that they have been associated with all three mutant isoforms of the RAS gene, although most series demonstrate predominance of NRAS61 [6,[17][18][19][20][21][22][23]. Further, the literature cites overall frequencies of RAS mutations in up to 48% of benign follicular adenomas (FA), 57% of FTC, and 21% of PTC (Table 1) [6, 18 -21, 24 -28].…”

Section: Prevalence and Isoform Pattern Of Ras Mutationsmentioning

confidence: 99%

“…This is because RAS mutations are consistently found in benign FA, leading some to even suggest that RAS-positive FA should be classified as "false-positive" molecular results [44]. However, this contrasts with the prevailing notion that RAS-positive FA is likely a precursor to RAS-positive follicular-patterned cancer [6,22,23,46].In tumors of follicular cell origin, RAS mutations are essentially restricted to FA, FTC, and FVPTC which are difficult to differentiate as benign or malignant based on cytology alone, and are therefore often indeterminate by FNAB. It is precisely in this group of FNAB results that RAS mutation testing may be most clinically useful.…”

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confidence: 99%

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RAS Mutations in Thyroid Cancer

Howell¹,

Hodak

Yip³

2013

The Oncologist

161

120

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In recent years, our understanding of the genetic alterations underlying thyroid oncogenesis has greatly expanded. The use of molecular markers, including RAS, in the management of thyroid carcinoma is also increasing. This review summarizes the current literature surrounding RAS and discusses its potential as a diagnostic and prognostic indicator in the management of thyroid cancer. The Oncologist 2013;18:926 -932 Implications for Practice: In recent years, our understanding of the molecular mechanisms underlying thyroid oncogenesis has greatly expanded. Further, the use of some molecular markers in the clinical management of thyroid cancer is increasing. Mutations in RAS represent the second most common genetic event in thyroid neoplasia. However, the significance of RAS-positive mutation status and the biological behavior of thyroid carcinomas that harbor RAS are not completely understood. The purposes of this review are to clarify the current literature surrounding RAS mutations in thyroid cancer and to examine the potential utility of RAS as a diagnostic tool to predict the presence of malignancy, thus altering subsequent clinical management. In addition, the prognostic value of RAS positivity in predicting the risk for tumor aggressiveness, recurrence, and mortality is discussed. INTRODUCTIONThyroid cancer (TC) is the most common endocrine malignancy, and its incidence is on the rise [1]. Tumors of follicular epithelial cell origin account for the vast majority of these cancers, and of these, well-differentiated papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) account for 95%; whereas, poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are observed far less frequently [2]. In recent years, our understanding of the molecular mechanisms underlying thyroid oncogenesis has greatly expanded, thus enabling differentiation of thyroid tumors based on characteristic genetic alterations in addition to traditional histologic criteria [3]. The most clinically relevant markers to date include point mutations in BRAF and RAS and RET/PTC and PAX8/PPAR␥ rearrangements. PTC is known to harbor BRAF most commonly, followed by RAS and RET/PTC, whereas FTC is characterized by the presence of either RAS or PAX8/PPAR␥ [3][4][5][6].The use of these molecular markers in the management of thyroid carcinoma is increasing. BRAF is perhaps the most studied of the markers and has emerged as an important diagnostic and prognostic tool. For example, the finding of BRAF in a thyroid nodule with indeterminate cytology is associated with a PTC risk of nearly 100%, and further, patients with BRAF-positive PTC are more likely to have aggressive and recurrent disease [7][8][9][10][11]. Likewise, RAS represents the second most common genetic mutation in TC and was first implicated in thyroid neoplasia more than two decades ago [12]. Despite this, the significance of RAS-positive mutation status and the biological behavior of thyroid carcinomas that harbor RAS are still not completely und...

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Aneuploidy and RAS mutations are mutually exclusive events in the development of well‐differentiated thyroid follicular tumours

Abstract: Our data suggest that aneuploidy and RAS mutations are mutually exclusive events in the development of well-differentiated thyroid follicular tumours.

Cited by 16 publications

References 43 publications

Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

The Putative PAX8/PPAR Fusion Oncoprotein Exhibits Partial Tumor Suppressor Activity through Up-Regulation of Micro-RNA-122 and Dominant-Negative PPAR Activity

RAS Mutations in Thyroid Cancer

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