<i>RAS</i>Mutations in Thyroid FNA Specimens Are Highly Predictive of Predominantly Low-Risk Follicular-Pattern Cancers

Gupta, Nikhil; Dasyam, Anil K.; Carty, Sally E.; Nikiforova, Marina N.; Ohori, N. Paul; Armstrong, Michaele J.; Yip, Linwah; LeBeau, Shane O.; McCoy, Kelly L.; Coyne, Christopher J.; Stang, Michael T.; Johnson, Jonas T.; Ferris, Robert L.; Seethala, Raja R.; Hodak, Steven P.

doi:10.1210/jc.2012-3396

Cited by 135 publications

(153 citation statements)

References 39 publications

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“…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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“…A study by Gupta et al in 46 patients with RAS-positive malignancy found bilateral cancer in 43% (n ϭ 20): 45% of these contralateral cancers were positive for RAS mutation, 5% were positive for BRAFV600E, and 50% did not undergo molecular testing. Notably, the majority of patients with bilateral cancer underwent diagnostic lobectomy as their initial procedure, resulting in the need for a second operative procedure in most [23].In some circumstances when the diagnosis of cancer is known preoperatively, total thyroidectomy is indicated. In the case of PTC, central neck dissection may also be considered because of the propensity of PTC to spread to central compartment lymph nodes and its association with recurrent disease [39,57].…”

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RAS Mutations in Thyroid Cancer

Howell¹,

Hodak

Yip³

2013

The Oncologist

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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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RAS Mutations in Thyroid Cancer

Howell¹,

Hodak

Yip³

2013

The Oncologist

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155

120

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“…Importantly, RAS alterations are not specific for thyroid malignant disease, occurring in 20-25% of follicular adenomas (Namba et al 1990, Liu et al 2008. Although follicular adenomas bearing mutated RAS are considered as lesions with high malignant potential (Gupta et al 2013), this strongly hampers the use of RAS status as molecular marker, both in the diagnostic and prognostic setting. To date, prognostic significance of RAS mutations in DTC has been addressed in few studies, with controversial results.…”

Section: Ras Mutationsmentioning

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Application of molecular biology of differentiated thyroid cancer for clinical prognostication

Marotta¹,

Sciammarella²,

Colao³

et al. 2016

Endocrine-Related Cancer

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Although cancer outcome results from the interplay between genetics and environment, researchers are making a great effort for applying molecular biology in the prognostication of differentiated thyroid cancer (DTC). Nevertheless, role of molecular characterisation in the prognostic setting of DTC is still nebulous. Among the most common and well-characterised genetic alterations related to DTC, including mutations of BRAF and RAS and RET rearrangements, BRAF V600E is the only mutation showing unequivocal association with clinical outcome. Unfortunately, its accuracy is strongly limited by low specificity. Recently, the introduction of next-generation sequencing techniques led to the identification of TERT promoter and TP53 mutations in DTC. These genetic abnormalities may identify a small subgroup of tumours with highly aggressive behaviour, thus improving specificity of molecular prognostication. Although knowledge of prognostic significance of TP53 mutations is still anecdotal, mutations of the TERT promoter have showed clear association with clinical outcome. Nevertheless, this genetic marker needs to be analysed according to a multigenetic model, as its prognostic effect becomes negligible when present in isolation. Given that any genetic alteration has demonstrated, taken alone, enough specificity, the co-occurrence of driving mutations is emerging as an independent genetic signature of aggressiveness, with possible future application in clinical practice. DTC prognostication may be empowered in the near future by non-tissue molecular prognosticators, including circulating BRAF V600E and miRNAs. Although promising, use of these markers needs to be refined by the technical sight, and the actual prognostic value is still yet to be validated. 23:11Review V Marotta et al. Molecular prognosis in thyroid cancer

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“…Sporadic medullary thyroid carcinomas with wild-type RET genes may harbor RAS mutations (HRAS or KRAS). 2,4,5,8,15,16 D. PIK3CA, AKT1, and TP53 Mutational Analysis PIK3CA, AKT1, and TP53 mutations are usually found in advanced thyroid cancer with propensity for dedifferentiation and distant metastasis. 8,17 E. CTNNB1 Mutational Analysis…”

Section: Ras Mutational Analysismentioning

confidence: 99%

Template for Reporting Results of Biomarker Testing of Specimens From Patients With Thyroid Carcinoma

Chiosea

Sylvia

Berman

et al. 2016

Archives of Pathology &Amp; Laboratory Medicine

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RASMutations in Thyroid FNA Specimens Are Highly Predictive of Predominantly Low-Risk Follicular-Pattern Cancers

Abstract: Introduction: RAS mutations are common in thyroid tumors and confer a high risk of cancer when detected in fine-needle aspiration (FNA) specimens. Specific characteristics of RAS-positive thyroid cancers are not well described.

Cited by 135 publications

References 39 publications

RAS Mutations in Thyroid Cancer

RAS Mutations in Thyroid Cancer

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

Template for Reporting Results of Biomarker Testing of Specimens From Patients With Thyroid Carcinoma

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