This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vasko, V. Articles by de Micco, C. Search for Related Content PubMed PubMed Citation Articles by Vasko, V. Articles by de Micco, C.

Specific Pattern of RAS Oncogene Mutations in Follicular Thyroid Tumors

Institut National de la Santé et de la Recherche Médicale U555 (V.V., M.F., J.D.C., P.C., J.F.H., C.d.M.), Department of Endocrine Surgery (J.F.H.), and Laboratory of Pathology (C.d.M.), Faculty of Medicine, Mediterranean University, Marseille, 13385 France; and Hospital for Endocrine Surgery (V.V.), Kiev, 252000 Ukraine

Address all correspondence and requests for reprints to: Dr. Catherine de Micco, Institut National de la Santé et de la Recherche Médicale U555, Faculté de Médecine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France. E-mail: cathy.demicco{at}medecine.univ-mrs.fr.

The prevalence of H-RAS, K-RAS, and N-RAS gene mutations in thyroid tumors according to malignancy and histology is controversial. Differences in methodology and histological classifications may explain discrepant results.

To address this issue, we first performed a pooled analysis of 269 mutations garnered from 39 previous studies. Mutations proved significantly less frequent when detected with direct sequencing than without (12.3% vs. 17%). The rate of mutation involving N-RAS exon 1 (N1) and K-RAS exon 2 (K2) was less than 1%. Mutations of codon 61 of N-RAS (N2) were significantly more frequent in follicular tumors (19%) than in papillary cancers (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. H-RAS mutations in codons 12/13 (H1) were found in 2–3% of all types of tumors, but H-RAS mutations in codon 61 (H2) were observed in only 1.4% of tumors, and almost all of them were malignant. K-RAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs. 1.6%) and were sometimes correlated with special epidemiological circumstances.

The second part of this study involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). We used direct sequencing after PCR amplification of exons 1 and 2 of the three RAS genes. Common and atypical adenomas were separated using strict cytological criteria. Mutations of H1-RAS were found in 12.5% of common adenomas and one follicular carcinoma (2.9%). Mutations of N2-RAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively. These results confirm the predominance of N2-RAS mutations in thyroid follicular tumors and their correlation with malignancy. They support the implication of N2-RAS mutations in the malignant progression of thyroid follicular tumors and the assumption that some atypical adenomas are precursors of follicular carcinomas.

This work was funded by a clinical research contract from Marseille Public Hospital System.

Abbreviations: AFA, Atypical follicular adenoma; FA, follicular adenoma; MIFC, minimally invasive follicular carcinoma; WIFC, widely invasive follicular carcinoma.

This article has been cited by other articles:

				A. Algeciras-Schimnich, D. Milosevic, B. McIver, H. Flynn, H. V. Reddi, N. L. Eberhardt, and S. K.G. Grebe Evaluation of the PAX8/PPARG Translocation in Follicular Thyroid Cancer with a 4-Color Reverse-Transcription PCR Assay and Automated High-Resolution Fragment Analysis Clin. Chem., March 1, 2010; 56(3): 391 - 398. [Abstract] [Full Text] [PDF]

				M. Xing Identifying Genetic Alterations in Poorly Differentiated Thyroid Cancer: A Rewarding Pursuit J. Clin. Endocrinol. Metab., December 1, 2009; 94(12): 4661 - 4664. [Full Text] [PDF]

				S. Hoshi, N. Hoshi, M. Okamoto, J. Paiz, T. Kusakabe, J. M. Ward, and S. Kimura Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice Carcinogenesis, September 1, 2009; 30(9): 1614 - 1619. [Abstract] [Full Text] [PDF]

				M. Fedele, D. Palmieri, G. Chiappetta, R. Pasquinelli, I. De Martino, C. Arra, G. Palma, T. Valentino, G. M Pierantoni, G. Viglietto, et al. Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice Endocr. Relat. Cancer, June 1, 2009; 16(2): 483 - 490. [Abstract] [Full Text] [PDF]

				J P. Couto, H Prazeres, P Castro, J Lima, V Maximo, P Soares, and M Sobrinho-Simoes How molecular pathology is changing and will change the therapeutics of patients with follicular cell-derived thyroid cancer J. Clin. Pathol., May 1, 2009; 62(5): 414 - 421. [Abstract] [Full Text] [PDF]

				Z. Liu, P. Hou, M. Ji, H. Guan, K. Studeman, K. Jensen, V. Vasko, A. K. El-Naggar, and M. Xing Highly Prevalent Genetic Alterations in Receptor Tyrosine Kinases and Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase Pathways in Anaplastic and Follicular Thyroid Cancers J. Clin. Endocrinol. Metab., August 1, 2008; 93(8): 3106 - 3116. [Abstract] [Full Text] [PDF]

				F Frasca, C Nucera, G Pellegriti, P Gangemi, M Attard, M Stella, M Loda, V Vella, C Giordano, F Trimarchi, et al. BRAF(V600E) mutation and the biology of papillary thyroid cancer Endocr. Relat. Cancer, March 1, 2008; 15(1): 191 - 205. [Abstract] [Full Text] [PDF]

				B. M Cavaco, P. F Batista, C. Martins, A. Banito, F. do Rosario, E. Limbert, L. G Sobrinho, and V. Leite Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations Endocr. Relat. Cancer, March 1, 2008; 15(1): 207 - 215. [Abstract] [Full Text] [PDF]

				A Salajegheh, E B Petcu, R A Smith, and A K-Y Lam Follicular variant of papillary thyroid carcinoma: a diagnostic challenge for clinicians and pathologists Postgrad. Med. J., February 1, 2008; 84(988): 78 - 82. [Abstract] [Full Text] [PDF]

				L. Santarpia, A. K. El-Naggar, G. J. Cote, J. N. Myers, and S. I. Sherman Phosphatidylinositol 3-Kinase/Akt and Ras/Raf-Mitogen-Activated Protein Kinase Pathway Mutations in Anaplastic Thyroid Cancer J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 278 - 284. [Abstract] [Full Text] [PDF]

				M. Xing BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Bases, and Clinical Implications Endocr. Rev., December 1, 2007; 28(7): 742 - 762. [Abstract] [Full Text] [PDF]

				O. M. Tsygankova, G. V. Prendergast, K. Puttaswamy, Y. Wang, M. D. Feldman, H. Wang, M. S. Brose, and J. L. Meinkoth Downregulation of Rap1GAP Contributes to Ras Transformation Mol. Cell. Biol., October 1, 2007; 27(19): 6647 - 6658. [Abstract] [Full Text] [PDF]

				Y. Wang, P. Hou, H. Yu, W. Wang, M. Ji, S. Zhao, S. Yan, X. Sun, D. Liu, B. Shi, et al. High Prevalence and Mutual Exclusivity of Genetic Alterations in the Phosphatidylinositol-3-Kinase/Akt Pathway in Thyroid Tumors J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2387 - 2390. [Abstract] [Full Text] [PDF]

				M. Xing Gene Methylation in Thyroid Tumorigenesis Endocrinology, March 1, 2007; 148(3): 948 - 953. [Abstract] [Full Text] [PDF]

				V. Vasko, A. V. Espinosa, W. Scouten, H. He, H. Auer, S. Liyanarachchi, A. Larin, V. Savchenko, G. L. Francis, A. de la Chapelle, et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion PNAS, February 20, 2007; 104(8): 2803 - 2808. [Abstract] [Full Text] [PDF]

				P. Hou, D. Liu, Y. Shan, S. Hu, K. Studeman, S. Condouris, Y. Wang, A. Trink, A. K. El-Naggar, G. Tallini, et al. Genetic Alterations and Their Relationship in the Phosphatidylinositol 3-Kinase/Akt Pathway in Thyroid Cancer Clin. Cancer Res., February 15, 2007; 13(4): 1161 - 1170. [Abstract] [Full Text] [PDF]

				K. A. B. Knostman, S. M. Jhiang, and C. C. Capen Genetic Alterations in Thyroid Cancer: The Role of Mouse Models Veterinary Pathology, January 1, 2007; 44(1): 1 - 14. [Abstract] [Full Text] [PDF]

				A. J. Fikaris, A. E. Lewis, A. Abulaiti, O. M. Tsygankova, and J. L. Meinkoth Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling J. Biol. Chem., November 17, 2006; 281(46): 34759 - 34767. [Abstract] [Full Text] [PDF]

				S. Matsukuma, M. Yoshihara, F. Kasai, A. Kato, A. Yoshida, M. Akaike, O. Kobayashi, H. Nakayama, Y. Sakuma, T. Yoshida, et al. Rapid and Simple Detection of Hot Spot Point Mutations of Epidermal Growth Factor Receptor, BRAF, and NRAS in Cancers Using the Loop-Hybrid Mobility Shift Assay J. Mol. Diagn., September 1, 2006; 8(4): 504 - 512. [Abstract] [Full Text] [PDF]

				J Di Cristofaro, M Silvy, A Lanteaume, M Marcy, P Carayon, and C De Micco Expression of tpo mRNA in thyroid tumors: quantitiative PCR analysis and correlation with alterations of ret, Braf , ras and pax8 genes. Endocr. Relat. Cancer, June 1, 2006; 13(2): 485 - 495. [Abstract] [Full Text] [PDF]

				A. Chiloeches and R. Marais Is BRAF the Achilles' Heel of Thyroid Cancer? Clin. Cancer Res., March 15, 2006; 12(6): 1661 - 1664. [Full Text] [PDF]

				B. Ouyang, J. A. Knauf, E. P. Smith, L. Zhang, T. Ramsey, N. Yusuff, D. Batt, and J. A. Fagin Inhibitors of Raf Kinase Activity Block Growth of Thyroid Cancer Cells with RET/PTC or BRAF Mutations In vitro and In vivo. Clin. Cancer Res., March 15, 2006; 12(6): 1785 - 1793. [Abstract] [Full Text] [PDF]

				T. Foukakis, A. Y. M. Au, G. Wallin, J. Geli, L. Forsberg, R. Clifton-Bligh, B. G. Robinson, W.-O. Lui, J. Zedenius, and C. Larsson The Ras Effector NORE1A Is Suppressed in Follicular Thyroid Carcinomas with a PAX8-PPAR{gamma} Fusion J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1143 - 1149. [Abstract] [Full Text] [PDF]

				P. Castro, A. P. Rebocho, R. J. Soares, J. Magalhaes, L. Roque, V. Trovisco, I. Vieira de Castro, M. Cardoso-de-Oliveira, E. Fonseca, P. Soares, et al. PAX8-PPAR{gamma} Rearrangement Is Frequently Detected in the Follicular Variant of Papillary Thyroid Carcinoma J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 213 - 220. [Abstract] [Full Text] [PDF]

				M. S. Sarquis, F. Weber, L. Shen, C. E. Broelsch, S. M. Jhiang, J. Zedenius, A. Frilling, and C. Eng High Frequency of Loss of Heterozygosity in Imprinted, Compared with Nonimprinted, Genomic Regions in Follicular Thyroid Carcinomas and Atypical Adenomas J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 262 - 269. [Abstract] [Full Text] [PDF]

				G. Wu, E. Mambo, Z. Guo, S. Hu, X. Huang, S. M. Gollin, B. Trink, P. W. Ladenson, D. Sidransky, and M. Xing Uncommon Mutation, but Common Amplifications, of the PIK3CA Gene in Thyroid Tumors J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4688 - 4693. [Abstract] [Full Text] [PDF]

				M Xing BRAF mutation in thyroid cancer Endocr. Relat. Cancer, June 1, 2005; 12(2): 245 - 262. [Abstract] [Full Text] [PDF]

				K. Wagner, R. Arciaga, A. Siperstein, M. Milas, I. Warshawsky, S. Sethu, K. Reddy, and M. K. Gupta Thyrotropin Receptor/Thyroglobulin Messenger Ribonucleic Acid in Peripheral Blood and Fine-Needle Aspiration Cytology: Diagnostic Synergy for Detecting Thyroid Cancer J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 1921 - 1924. [Abstract] [Full Text] [PDF]

				J Di Cristofaro, V Vasko, V Savchenko, S Cherenko, A Larin, M D Ringel, M Saji, M Marcy, J F Henry, P Carayon, et al. ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients Endocr. Relat. Cancer, March 1, 2005; 12(1): 173 - 183. [Abstract] [Full Text] [PDF]

				J. Kohrle Guard Your Master: Thyroid Hormone Receptors Protect Their Gland of Origin from Thyroid Cancer Endocrinology, October 1, 2004; 145(10): 4427 - 4429. [Full Text] [PDF]

				P. Chinnappa, L. Taguba, R. Arciaga, C. Faiman, A. Siperstein, A. E. Mehta, S. K. Reddy, C. Nasr, and M. K. Gupta Detection of Thyrotropin-Receptor Messenger Ribonucleic Acid (mRNA) and Thyroglobulin mRNA Transcripts in Peripheral Blood of Patients with Thyroid Disease: Sensitive and Specific Markers for Thyroid Cancer J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3705 - 3709. [Abstract] [Full Text] [PDF]

				M. Xing, V. Vasko, G. Tallini, A. Larin, G. Wu, R. Udelsman, M. D. Ringel, P. W. Ladenson, and D. Sidransky BRAF T1796A Transversion Mutation in Various Thyroid Neoplasms J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1365 - 1368. [Abstract] [Full Text] [PDF]