Abstract
Rearrangement of the RET gene, also known as RET/PTC rearrangement, is the most common genetic alteration identified to date in thyroid papillary carcinomas. The prevalence of RET/PTC in papillary carcinomas shows significant geographic variation and is approx 35% in North America. RET/PTC is more common in tumors in children and young adults, and in papillary carcinomas associated with radiation exposure. There are at least 10 different types of RET/PTC, all resulting from the fusion of the tyrosine kinase domain of RET to the 5′ portion of different genes. RET/PTC1 and RET/PTC3 are the most common types, accounting for >90% of all rearrangements. There is some evidence that different types of RET/PTC may be associated with distinct biologic properties of papillary carcinomas. RET/PTC1 tends to be more common in tumors with typical papillary growth and microcarcinomas and to have a more benign clinical course, whereas RET/PTC3 in some populations shows a strong correlation with the solid variant of papillary carcinoma and more aggressive tumor behavior. RET/PTC has recently been found in hyalinizing trabecular adenomas of the thyroid gland, providing molecular evidence in favor of this tumor to be a variant of papillary carcinoma. The occurrence of RET/PTC in Hashimoto thyroiditis and thyroid follicular adenomas and hyperplastic nodules reported in several studies has not been confirmed in other observations and remains controversial.
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References
Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42:581–588, 1985.
Takahashi M. Structure and expression of the ret transforming gene. IARC Sci Publ 189–197, 1988.
Airaksinen MS, Titievsky A, Saarma M. GDNF family neurotrophic factor signaling: four masters, one servant? Mol Cell Neurosci 13:313–325, 1999.
Schuchardt A, D’Agati V, Larsson-Blomberg L, et al. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380–383, 1994.
Smith DP, Eng C, Ponder BA. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes and Hirschsprung disease. J Cell Sci Suppl 18:43–49, 1994.
Grieco M, Santoro M, Berlingieri MT, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563, 1990.
Santoro M, Dathan NA, Berlingieri MT, et al. Molecular characterization of RET/PTC3: a novel rearranged version of the RET protooncogene in a human thyroid papillary carcinoma. Oncogene 9:509–516, 1994.
Bongarzone I, Butti MG, Coronelli S, et al. Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. Cancer Res 54:2979–2985, 1994.
Pierotti MA, Santoro M, Jenkins RB, et al. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci USA 89:1616–1620, 1992.
Minoletti F, Butti MG, Coronelli S, et al. The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2. Genes Chromosomes Cancer 11:51–57, 1994.
Bongarzone I, Monzini N, Borrello MG, et al. Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Mol Cell Biol 13:358–366, 1993.
Klugbauer S, Demidchik EP, Lengfelder E, et al. Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5. Cancer Res 58:198–203, 1998.
Klugbauer S, Rabes HM. The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncogene 18:4388–4393, 1999.
Nakata T, Kitamura Y, Shimizu K, et al. Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a papillary thyroid carcinoma. Genes Chromosomes Cancer 25:97–103, 1999.
Klugbauer S, Jauch A, Lengfelder E, et al. A novel type of RET rearrangement (PTC8) in childhood papillary thyroid carcinomas and characterization of the involved gene (RFG8). Cancer Res 60:7028–7032, 2000.
Salassidis K, Bruch J, Zitzelsberger H, et al. Translocation t(10;14)(q11.2:q22.1) fusing the kinetin to the RET gene creates a novel rearranged form (PTC8) of the RET protooncogene in radiation-induced childhood papillary thyroid carcinoma. Cancer Res 60:2786–2789, 2000.
Corvi R, Berger N, Balczon R, et al. RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene 19:4236–4242, 2000.
Tong Q, Xing S, Jhiang SM. Leucine zipper-mediated dimerization is essential for the PTC1 oncogenic activity. J Biol Chem 272:9043–9047, 1997.
Jhiang SM. The RET proto-oncogene in human cancers. Oncogene 19:5590–5597, 2000.
Salvatore D, Barone MV, Salvatore G, et al. Tyrosines 1015 and 1062 are in vivo autophosphorylation sites in ret and ret-derived oncoproteins. J Clin Endocrinol Metab 85:3898–3907, 2000.
Pierotti MA, Bongarzone I, Borello MG, et al. Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 16:1–14, 1996.
Monaco C, Visconti R, Barone MV, et al. The RFG oligomerization domain mediates kinase activation and re-localization of the RET/PTC3 oncoprotein to the plasma membrane. Oncogene 20:599–608, 2001.
Jhiang SM, Sagartz JE, Tong Q, et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137:375–378, 1996.
Santoro M, Chiappetta G, Cerrato A, et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–1826, 1996.
Powell DJ Jr., Russell J, Nibu K, et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 58:5523–5528, 1998.
Santoro M, Melillo RM, Grieco M, et al. The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. Cell Growth Differ 4:77–84, 1993.
Fischer AH, Bond JA, Taysavang P, et al. Papillary thyroid carcinoma oncogene (RET/PTC) alters the nuclear envelope and chromatin structure. Am J Pathol 153:1443–1450, 1998.
Jenkins RB, Hay ID, Herath JF, et al. Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Cancer 66:1213–1220, 1990.
Sozzi G, Bongarzone I, Miozzo M, et al. Cytogenetic and molecular genetic characterization of papillary thyroid carcinomas. Genes Chromosomes Cancer 5:212–218, 1992.
Santoro M, Carlomagno F, Hay ID, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 89:1517–1522, 1992.
Cinti R, Yin L, Ilc K, et al. RET rearrangements in papillary thyroid carcinomas and adenomas detected by interphase FISH. Cytogenet Cell Genet 88:56–61, 2000.
Corvi R, Lesueur F, Martinez-Alfaro M, et al. RET rearrangements in familial papillary thyroid carcinomas. Cancer Lett 170:191–198, 2001.
Jhiang SM, Smanik PA, Mazzaferri EL. Development of a single-step duplex RT-PCR detecting different forms of ret activation, and identification of the third form of in vivo ret activation in human papillary thyroid carcinoma. Cancer Lett 78:69–76, 1994.
Nikiforov YE, Rowland JM, Bove KE, et al. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 57:1690–1694, 1997.
Tallini G, Ghossein RA, Emanuel J, et al. Detection of thyroglobulin, thyroid peroxidase, and RET/PTC1 mRNA transcripts in the peripheral blood of patients with thyroid disease. J Clin Oncol 16:1158–1166, 1998.
Fabien N, Paulin C, Santoro M, et al. Detection of RET oncogene activation in human papillary thyroid carcinomas by in situ hybridisation. Br J Cancer 66:1094–1098, 1992.
Lam AK, Montone KT, Nolan KA, et al. Ret oncogene activation in papillary thyroid carcinoma: prevalence and implication on the histological parameters. Hum Pathol 29:565–568, 1998.
Cheung CC, Ezzat S, Freeman JL, et al. Immunohistochemical diagnosis of papillary thyroid carcinoma. Mod Pathol 14:338–342, 2001.
Tallini G, Santoro M, Helie M, et al. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 4:287–294, 1998.
Santoro M, Sabino N, Ishizaka Y, et al. Involvement of RET oncogene in human tumours: specificity of RET activation to thyroid tumours. Br J Cancer 68:460–464, 1993.
Ishizaka Y, Kobayashi S, Ushijima T, et al. Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT-PCR method. Oncogene 6:1667–1672, 1991.
Bounacer A, Wicker R, Caillou B, et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene 15:1263–1273, 1997.
Wirtschafter A, Schmidt R, Rosen D, et al. Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope 107:95–100, 1997.
Sheils OM, O’Eary JJ, Uhlmann V, et al. ret/PTC-1 activation in Hashimoto thyroiditis. Int J Surg Pathol 8:185–189, 2000.
Elisei R, Romei C, Vorontsova T, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab 86:3211–3216, 2001.
Jhiang SM, Caruso DR, Gilmore E, et al. Detection of the PTC/retTPC oncogene in human thyroid cancers. Oncogene 7:1331–1337, 1992.
Nikiforova MN, Caudill CM, Biddinger BW, et al. Prevalence of RET/PTC rearrangements in Hashimoto’s thyroiditis and papillary thyroid carcinomas. Int J Surg Pathol 10:15–22, 2002.
Sugg SL, Ezzat S, Zheng L, et al. Oncogene profile of papillary thyroid carcinoma. Surgery 125:46–52, 1999.
Bongarzone I, Fugazzola L, Vigneri P, et al. Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma. J Clin Endocrinol Metab 81:2006–2009, 1996.
Bongarzone I, Vigneri P, Mariani L, et al. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin Cancer Res 4:223–228, 1998.
Zou M, Shi Y, Farid NR. Low rate of ret protooncogene activation (PTC/retTPC) in papillary thyroid carcinomas from Saudi Arabia. Cancer 73:176–180, 1994.
Chua EL, Wu WM, Tran KT, et al. Prevalence and distribution of ret/ptc 1, 2, and 3 in papillary thyroid carcinoma in New Caledonia and Australia. J Clin Endocrinol Metab 85:2733–2739, 2000.
Wajjwalku W, Nakamura S, Hasegawa Y, et al. Low frequency of rearrangements of the ret and trk proto-oncogenes in Japanese thyroid papillary carcinomas. Jpn J Cancer Res 83:671–675, 1992.
Motomura T, Nikiforov YE, Namba H, et al. RET rearrangements in Japanese pediatric and adult papillary thyroid cancers. Thyroid 8:485–489, 1998.
Learoyd DL, Messina M, Zedenius J, et al. RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas. J Clin Endocrinol Metab 83:3631–3635, 1998.
Klugbauer S, Demidchik EP, Lengfelder E, et al. Molecular analysis of new subtypes of ELE/RET rearrangements, their reciprocal transcripts and breakpoints in papillary thyroid carcinomas of children after Chernobyl. Oncogene 16:671–675, 1998.
Rabes HM. Gene rearrangements in radiation-induced thyroid carcinogenesis. Med Pediatr Oncol 36:574–582, 2001.
Sugg SL, Ezzat S, Rosen IB, et al. Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 83:4116–4122, 1998.
Fenton CL, Lukes Y, Nicholson D, et al. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J Clin Endocrinol Metab 85:1170–1175, 2000.
Rabes HM, Demidchik EP, Sidorow JD, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-Chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 6:1093–1103, 2000.
Soares P, Fonseca E, Wynford-Thomas D, et al. Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms? J Pathol 185:71–78, 1998.
Fugazzola L, Pilotti S, Pinchera A, et al. Oncogenic rearrangements of the RET protooncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res 55:5617–5620, 1995.
Klugbauer S, Lengfelder E, Demidchik EP, et al. High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. Oncogene 11:2459–2467, 1995.
Smida J, Salassidis K, Hieber L, et al. Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus. Int J Cancer 80:32–38, 1999.
Ito T, Seyama T, Iwamoto KS, et al. In vitro irradiation is able to cause RET oncogene rearrangement. Cancer Res 53:2940–2943, 1993.
Mizuno T, Kyoizumi S, Suzuki T, et al. Continued expression of a tissue specific activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis. Oncogene 15:1455–1460, 1997.
Mizuno T, Iwamoto KS, Kyoizumi S, et al. Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene 19:438–443, 2000.
Nikiforova MN, Stringer JR, Blough R, et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290:138–141, 2000.
Viglietto G, Chiappetta G, Martinez-Tello FJ, et al. RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 11:1207–1210, 1995.
Cheung CC, Ezzat S, Ramyar L, et al. Molecular basis of hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab 85:878–882, 2000.
Cetta F, Olschwang S, Petracci M, et al. Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection. World J Surg 22:1231–1236, 1998.
Soravia C, Sugg SL, Berk T, et al. Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study. Am J Pathol 154:127–135, 1999.
Thomas GA, Bunnell H, Cook HA, et al. High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab 84:4232–4238, 1999.
Nikiforov YE, Erickson LA, Nikiforova MN, et al. Solid variant of papillary thyroid carcinoma: incidence, clinical-pathologic characteristics, molecular analysis, and biologic behavior. Am J Surg Pathol 25:1478–1484, 2001.
Mayr B, Brabant G, Goretzki P, et al. ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? J Clin Endocrinol Metab 82:1306, 1307, 1997.
Nikiforov YE, Bove KE, Rowland JM, et al. RET/PTC1 and RET/PTC3 rearrangements are associated with different biological behavior of papillary thyroid carcinoma. Mod Pathol 13:73A, 2000 (abstract).
Cetta F, Gori M, Montalto G, et al. Different significance of ret/PTC(1) and ret/PTC(3) rearrangements in thyroid carcinogenesis: lesson from two subgroups of patients with papillary thyroid carcinomas showing the highest incidence of ret/PTC activation. J Clin Endocrinol Metab 86:1429, 2001.
Sagartz JE, Jhiang SM, Tong Q, et al. Thyroid-stimulating hormone promotes growth of thyroid carcinomas in transgenic mice with targeted expression of the ret/PTC1 oncogene. Lab Invest 76:307–318, 1997.
Carney JA, Ryan J, Goellner JR. Hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol 11:583–591, 1987.
Bronner MP, LiVolsi VA, Jennings TA. PLAT: paraganglioma-like adenomas of the thyroid. Surg Pathol 1:383–389, 1988.
Rosai J, Carcangiu ML, DeLellis RA. Tumors of the thyroid. Washington, DC: AFIP, 1992.
Papotti M, Volante M, Giuliano A, et al. RET/PTC activation in hyalinizing trabecular tumors of the thyroid. Am J Surg Pathol 24:1615–1621, 2000.
Cheung CC, Boerner SL, MacMillan CM, et al. Hyalinizing trabecular tumor of the thyroid: a variant of papillary carcinoma proved by molecular genetics. Am J Surg Pathol 24:1622–1626, 2000.
Walker RP, Paloyan E. The relationship between Hashimoto’s thyroiditis, thyroid neoplasia, and primary hyperparathyroidism. Otolaryngol Clin North Am 23:291–302, 1990.
Crile G, Jr. Struma lymphomatosa and carcinoma of the thyroid. Surg Gynecol Obstet 147:350–352, 1978.
Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med 312:601–604, 1985.
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Nikiforov, Y.E. RET/PTC rearrangement in thyroid tumors. Endocr Pathol 13, 3–16 (2002). https://doi.org/10.1385/EP:13:1:03
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DOI: https://doi.org/10.1385/EP:13:1:03