| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Rearrangement in Thyroid Tumors: Evidence for Distinct Molecular Pathways in Thyroid Follicular Carcinoma
Department of Pathology and Laboratory Medicine (M.N.N., P.W.B., Y.E.N.) and Division of Cardiology (R.A.L., G.W.D.), University of Cincinnati, Cincinnati, Ohio 45267-0529; Department of Medicine (E.K.A.), Brigham and Women’s Hospital, Boston, Massachusetts 02115; Department of Pathology (G.T.), Yale University School of Medicine, New Haven, Connecticut 06510; and Department of Pathology and Laboratory Medicine (T.G.K.), Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia 30322
Address all correspondence and requests for reprints to: Dr. Yuri Nikiforov, Department of Pathology, University of Cincinnati, 231 Albert Sabin Way, P.O. Box 670529, Cincinnati, Ohio 45267-0529. E-mail: yuri.nikiforov{at}uc.edu.
A series of 88 conventional follicular and Hürthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR
rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry. A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS, K-RAS, and N-RAS genes. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPAR rearrangement, and only one (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPAR rearrangement, and 48% had neither. Follicular carcinomas with PAX8-PPAR typically showed immunoreactivity for galectin-3 but not for HBME-1, tended to present at a younger patient age and be smaller size, and were almost always overtly invasive. In contrast, follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hürthle cell tumors infrequently had PAX8-PPAR rearrangement or RAS mutations. These results suggest that conventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR rearrangement.
This work was supported by NIH Grants R01-CA88041 (to Y.N.) and CA75425 and a Georgia Cancer Coalition Distinguished Clinical Scientist Award (to T.G.K.). Tissue samples were collected in part using a support by a grant from the NIH (PHS M01 RR08084, the Children’s Hospital–University of Cincinnati General Clinical Research Center Tissue Procurement Facility) and through the Cooperative Human Tissue Network (CHTN), which is funded by the National Cancer Institute.
Abbreviations: FMCA, Fluorescence melting curve analysis; FNA, fine-needle aspiration; PPAR, peroxisome proliferator-activated receptor; Tm, melting temperature.
This article has been cited by other articles:
 |
|
 |
|
  J. C. Ricarte-Filho, M. Ryder, D. A. Chitale, M. Rivera, A. Heguy, M. Ladanyi, M. Janakiraman, D. Solit, J. A. Knauf, R. M. Tuttle, et al. Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles for BRAF, PIK3CA, and AKT1 Cancer Res., June 1, 2009; 69(11): 4885 - 4893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. E. Nikiforov, D. L. Steward, T. M. Robinson-Smith, B. R. Haugen, J. P. Klopper, Z. Zhu, J. A. Fagin, M. Falciglia, K. Weber, and M. N. Nikiforova Molecular Testing for Mutations in Improving the Fine-Needle Aspiration Diagnosis of Thyroid Nodules J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 2092 - 2098. [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]
|
|
|
|
 |
|
 R. T. Kloos, M. D. Ringel, M. V. Knopp, N. C. Hall, M. King, R. Stevens, J. Liang, P. E. Wakely Jr, V. V. Vasko, M. Saji, et al. Phase II Trial of Sorafenib in Metastatic Thyroid Cancer J. Clin. Oncol., April 1, 2009; 27(10): 1675 - 1684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Karger, C. Weidinger, K. Krause, S.-Y. Sheu, T. Aigner, O. Gimm, K.-W. Schmid, H. Dralle, and D. Fuhrer FOXO3a: a novel player in thyroid carcinogenesis? Endocr. Relat. Cancer, March 1, 2009; 16(1): 189 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Beadling, E. Jacobson-Dunlop, F. S. Hodi, C. Le, A. Warrick, J. Patterson, A. Town, A. Harlow, F. Cruz III, S. Azar, et al. KIT Gene Mutations and Copy Number in Melanoma Subtypes Clin. Cancer Res., November 1, 2008; 14(21): 6821 - 6828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Eszlinger, K. Krohn, S. Hauptmann, H. Dralle, T. J. Giordano, and R. Paschke Perspectives for Improved and More Accurate Classification of Thyroid Epithelial Tumors J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3286 - 3294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Nikiforova, G. C. Tseng, D. Steward, D. Diorio, and Y. E. Nikiforov MicroRNA Expression Profiling of Thyroid Tumors: Biological Significance and Diagnostic Utility J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1600 - 1608. [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]
|
|
|
|
|
|
G. Riesco-Eizaguirre and P. Santisteban New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy Endocr. Relat. Cancer, December 1, 2007; 14(4): 957 - 977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-M. Wang, Y.-W. Huang, J.-S. Huang, C.-H. Wang, V. C. Kok, C.-M. Hung, H.-M. Chen, and C.-Y. Tzen Anaplastic Carcinoma of the Thyroid Arising More Often from Follicular Carcinoma than Papillary Carcinoma Ann. Surg. Oncol., October 1, 2007; 14(10): 3011 - 3018. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-J. Oh, V. Rishi, S. Pelech, and C. Vinson Histological and proteomic analysis of reversible H-RasV12G expression in transgenic mouse skin Carcinogenesis, October 1, 2007; 28(10): 2244 - 2252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ulisse, E. Baldini, M. Toller, J.-G. Delcros, A. Gueho, F. Curcio, E. De Antoni, L. Giacomelli, F. S Ambesi-Impiombato, S. Bocchini, et al. Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues Endocr. Relat. Cancer, September 1, 2007; 14(3): 827 - 837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Eszlinger, K. Krohn, A. Kukulska, B. Jarzab, and R. Paschke Perspectives and Limitations of Microarray-Based Gene Expression Profiling of Thyroid Tumors Endocr. Rev., May 1, 2007; 28(3): 322 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Krause, S. Karger, A. Schierhorn, S. Poncin, M.-C. Many, and D. Fuhrer Proteomic Profiling of Cold Thyroid Nodules Endocrinology, April 1, 2007; 148(4): 1754 - 1763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. V. Reddi, B. McIver, S. K. G. Grebe, and N. L. Eberhardt The Paired Box-8/Peroxisome Proliferator-Activated Receptor-{gamma} Oncogene in Thyroid Tumorigenesis Endocrinology, March 1, 2007; 148(3): 932 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Michalik, J. Auwerx, J. P. Berger, V. K. Chatterjee, C. K. Glass, F. J. Gonzalez, P. A. Grimaldi, T. Kadowaki, M. A. Lazar, S. O'Rahilly, et al. International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors Pharmacol. Rev., December 1, 2006; 58(4): 726 - 741. [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]
|
|
|
|
|
|
M Niedziela Pathogenesis, diagnosis and management of thyroid nodules in children. Endocr. Relat. Cancer, June 1, 2006; 13(2): 427 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Bakhsh, G Kirov, J W Gregory, E D Williams, and M Ludgate A new form of familial multi-nodular goitre with progression to differentiated thyroid cancer. Endocr. Relat. Cancer, June 1, 2006; 13(2): 475 - 483. [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]
|
|
|
|
|
|
G. Cohen, R. Mustafi, A. Chumsangsri, N. Little, J. Nathanson, S. Cerda, S. Jagadeeswaran, U. Dougherty, L. Joseph, J. Hart, et al. Epidermal Growth Factor Receptor Signaling Is Up-regulated in Human Colonic Aberrant Crypt Foci Cancer Res., June 1, 2006; 66(11): 5656 - 5664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Giordano, A. Y.M. Au, R. Kuick, D. G. Thomas, D. R. Rhodes, K. G. Wilhelm Jr., M. Vinco, D. E. Misek, D. Sanders, Z. Zhu, et al. Delineation, Functional Validation, and Bioinformatic Evaluation of Gene Expression in Thyroid Follicular Carcinomas with the PAX8-PPARG Translocation. Clin. Cancer Res., April 1, 2006; 12(7): 1983 - 1993. [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]
|
|
|
|
|
|
A. Y. M. Au, C. McBride, K. G. Wilhelm Jr., R. J. Koenig, B. Speller, L. Cheung, M. Messina, J. Wentworth, V. Tasevski, D. Learoyd, et al. PAX8-Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Disrupts Normal PAX8 or PPAR{gamma} Transcriptional Function and Stimulates Follicular Thyroid Cell Growth Endocrinology, January 1, 2006; 147(1): 367 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B Jarzab, D Handkiewicz-Junak, and J Wloch Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review Endocr. Relat. Cancer, December 1, 2005; 12(4): 773 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Castro, L. Roque, J. Magalhaes, and M. Sobrinho-Simoes A Subset of the Follicular Variant of Papillary Thyroid Carcinoma Harbors the PAX8-PPAR{gamma} Translocation International Journal of Surgical Pathology, July 1, 2005; 13(3): 235 - 238. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Lacroix, V. Lazar, S. Michiels, H. Ripoche, P. Dessen, M. Talbot, B. Caillou, J.-P. Levillain, M. Schlumberger, and J.-M. Bidart Follicular Thyroid Tumors with the PAX8-PPAR{gamma}1 Rearrangement Display Characteristic Genetic Alterations Am. J. Pathol., July 1, 2005; 167(1): 223 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Saggiorato, R De Pompa, M Volante, S Cappia, F Arecco, A P Dei Tos, F Orlandi, and M Papotti Characterization of thyroid 'follicular neoplasms' in fine-needle aspiration cytological specimens using a panel of immunohistochemical markers: a proposal for clinical application Endocr. Relat. Cancer, June 1, 2005; 12(2): 305 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Krohn, D. Fuhrer, Y. Bayer, M. Eszlinger, V. Brauer, S. Neumann, and R. Paschke Molecular Pathogenesis of Euthyroid and Toxic Multinodular Goiter Endocr. Rev., June 1, 2005; 26(4): 504 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Fuhrer, M Eszlinger, S Karger, K Krause, C Engelhardt, D Hasenclever, H Dralle, and R Paschke Evaluation of insulin-like growth factor II, cyclooxygenase-2, ets-1 and thyroid-specific thyroglobulin mRNA expression in benign and malignant thyroid tumours Eur. J. Endocrinol., May 1, 2005; 152(5): 785 - 790. [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]
|
|
|
|
|
|
M. L. Motti, D. Califano, G. Troncone, C. De Marco, I. Migliaccio, E. Palmieri, L. Pezzullo, L. Palombini, A. Fusco, and G. Viglietto Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway: Regulation of p27kip1 Expression and Localization Am. J. Pathol., March 1, 2005; 166(3): 737 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sahin, B. L. Allard, M. Yates, J. G. Powell, X.-L. Wang, I. D. Hay, Y. Zhao, J. R. Goellner, T. J. Sebo, S. K. G. Grebe, et al. PPAR{gamma} Staining as a Surrogate for PAX8/PPAR{gamma} Fusion Oncogene Expression in Follicular Neoplasms: Clinicopathological Correlation and Histopathological Diagnostic Value J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 463 - 468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kumagai, H. Namba, V. A. Saenko, K. Ashizawa, A. Ohtsuru, M. Ito, N. Ishikawa, K. Sugino, K. Ito, S. Jeremiah, et al. Low Frequency of BRAFT1796A Mutations in Childhood Thyroid Carcinomas J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4280 - 4284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Aldred, Y. Huang, S. Liyanarachchi, N. S. Pellegata, O. Gimm, S. Jhiang, R. V. Davuluri, A. de La Chapelle, and C. Eng Papillary and Follicular Thyroid Carcinomas Show Distinctly Different Microarray Expression Profiles and Can Be Distinguished by a Minimum of Five Genes J. Clin. Oncol., September 1, 2004; 22(17): 3531 - 3539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Greco, R. Vona, M. Cosimelli, P. Matarrese, E. Straface, P. Scordati, D. Giannarelli, V. Casale, D. Assisi, M. Mottolese, et al. Cell surface overexpression of galectin-3 and the presence of its ligand 90k in the blood plasma as determinants in colon neoplastic lesions Glycobiology, September 1, 2004; 14(9): 783 - 792. [Abstract] [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]
|
|
|
|
|
|
C. Torres-Cabala, A. Panizo-Santos, H. C. Krutzsch, H. Barazi, M. Namba, M. Sakaguchi, D. D. Roberts, and M. J. Merino Differential Expression of S100C in Thyroid Lesions International Journal of Surgical Pathology, April 1, 2004; 12(2): 107 - 115. [Abstract] [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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
