Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant

Cristofaro, Julie Di; Marcy, M.; Vasko, Vasily; Sébag, F.; Fakhry, Nicolas; Wynford-Thomas, David; Micco, C. De

doi:10.1016/j.humpath.2006.01.030

Cited by 90 publications

(55 citation statements)

References 31 publications

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“…However, both mutations have been detected by other authors in tumours from other tissues, thus confirming their oncogenic role (Forbes et al 2006). The N-RAS Q61R mutation, herein identified in two familial tumours (one classic PTC and one PTCfv), has been described in 21-30% of sporadic PTCfv but not in classic PTC , Di Cristofaro et al 2006.…”

Section: Discussionsupporting

confidence: 81%

Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations

Cavaco¹,

Batista²,

Martins³

et al. 2008

Endocrine Related Cancer

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Linkage analysis has identified four familial non-medullary thyroid carcinoma (FNMTC) susceptibility loci: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32) and TCO (19p13.2). To date, there is no evidence for the involvement of genes from the RAS/RAF signalling pathway in FNMTC. The aim of our study was to evaluate the role of the four susceptibility loci, and RAS/RAF signalling pathway genes, in FNMTC. In total, 8 FNMTC families, and 27 thyroid lesions from family members (22 papillary thyroid carcinomas (PTCs): 11 classic, 10 of the follicular variant and 1 of the mixed variant; 4 follicular thyroid adenomas (FTAs) and 1 nodular goitre (NG)), were evaluated for the involvement of the four susceptibility regions, using linkage and loss of heterozygosity (LOH) analyses. BRAF and H-, N-and K-RAS mutations were also screened in the 27 lesions and patients. Linkage analysis in seven informative families showed no evidence for the involvement of any of the four candidate regions, supporting a genetic heterogeneity for FNMTC. Twenty tumours (74%), of which 18 were PTCs, showed no LOH at the four susceptibility loci. The remaining seven tumours (four PTCs, two FTAs and one NG) showed variable patterns of LOH. Fourteen tumours (52%) had somatic mutations: BRAF-V600E mutation was observed in 9 out of the 22 PTCs (41%); and H-RAS and N-RAS mutations were detected in 5 out of the 22 PTCs (23%). Our data suggest that the four candidate regions are not frequently involved in FNMTC and that the somatic activation of BRAF and RAS plays a role in FNMTC tumourigenesis.

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Section: Discussionsupporting

confidence: 81%

Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations

Cavaco¹,

Batista²,

Martins³

et al. 2008

Endocrine Related Cancer

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“…With respect to papillary cancer, RAS mutations are generally restricted to the follicular variant subtype, as previously mentioned [21,23,26]. Furthermore, the most common alterations found in non-FVPTC, BRAF V600E and RET/PTC, are infrequent in FVPTC, again suggesting a distinct RAS-mediated mechanism for tumorigenesis in PTC [26,33]. The precursor lesion for RAS-mediated development of FTC and FVPTC is currently hypothesized to be RAS-positive FA [3,4,6].…”

Section: Pathogenesis Of Ras-positive Thyroid Carcinomamentioning

confidence: 94%

RAS Mutations in Thyroid Cancer

Howell¹,

Hodak

Yip³

2013

The Oncologist

155

121

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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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“…The primers flanking exon 15 of the BRAF gene were 5 0 -TC C-TTT-ACT-TAC-ACC-TCA-G-3 0 and CAT-CTC-AGG-GC C-AAA-AAT-3 0 . Exon 2 of the N-Ras gene was amplified using primer sequences described elsewhere (Di Cristofaro et al, 2006). Amplified fragments were purified and directly sequenced on a CEQ 8000 apparatus, using a CEQ DTCS Quick Start Kit (Beckman Coulter, Fullerton, CA, USA) following the manufacturer's instructions.…”

Section: Data Analysis and Statistical Methodsmentioning

confidence: 99%

Microarray analysis refines classification of non-medullary thyroid tumours of uncertain malignancy

et al. 2007

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Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant

Cited by 90 publications

References 31 publications

Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations

Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations

RAS Mutations in Thyroid Cancer

Microarray analysis refines classification of non-medullary thyroid tumours of uncertain malignancy

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