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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3631-3635
Copyright © 1998 by The Endocrine Society

Original Studies

RET/PTC and RET Tyrosine Kinase Expression in Adult Papillary Thyroid Carcinomas1

Diana L. Learoyd, Marinella Messina, Jan Zedenius, Ana I. Guinea, Leigh W. Delbridge and Bruce G. Robinson

Molecular Genetics Unit, Kolling Institute of Medical Research (D.L.L., M.M., B.G.R.), and the Departments of Endocrinology (D.L.L., B.G.R.) and Surgery (A.I.G., L.W.D.), Royal North Shore Hospital and University of Sydney, Sydney, Australia; and the Department of Surgery, Karolinska Hospital (J.Z.), Stockholm, Sweden

Address all correspondence and requests for reprints to: Prof. B. G. Robinson, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. E-mail: bgr{at}med.usyd.edu.au


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The prevalence of RET/PTC rearrangements in papillary thyroid carcinomas (PTCs) varies widely in different studies, and an association of RET/PTC presence with tumor behavior remains to be clarified. A prospective study of 50 adult PTCs examined, using RT-PCR, the prevalence of the 3 main RET rearrangements and also of RET tyrosine kinase (TK) domain sequence expression. The genetic findings were correlated with the MACIS clinical prognostic score and with individual clinical parameters. Three of the patients had been exposed to radiation in childhood or adolescence. Four of the PTCs contained RET/PTC1, confirmed by sequencing, and none contained RET/PTC2 or RET/PTC3. The prevalence of RET rearrangements overall was 8%, but in the subgroup of 3 radiation-exposed patients it was 66.6%. Interestingly, RET tyrosine kinase domain messenger ribonucleic acid was detectable in 70% of PTCs using RET exon 12/13 primers and was detectable in 24% of PTCs using RET exon 15/17 primers. RT-PCR for calcitonin and RET extracellular domain, however, was negative. There was no association between the presence or absence of RET/PTC in the patient’s tumor and clinical parameters. We conclude that RET/PTC1 is the predominant rearrangement in PTCs from adults with a history of external irradiation in childhood. RET TK messenger ribonucleic acid expression is common in PTCs, using RT-PCR, and cannot be used to infer the presence of specific RET rearrangements or of RET activation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE RET protooncogene encodes a tyrosine kinase cell surface receptor and has an important role in the pathogenesis of some thyroid tumors. RET/PTCs are rearranged forms of RET found in papillary thyroid carcinoma (PTC) (1, 2), and they comprise three main forms (3, 4, 5, 6, 7). Two variations of RET/PTC3 have been described (8, 9); one is designated RET/PTC4 (8), and RET/PTC5 has been described recently in two PTC cases from areas contaminated by the Chernobyl nuclear accident (10). RET/PTC1 and RET/PTC3 arise from chromosome 10 inversions (11, 12), whereas the rarer RET/PTC2 arises from a chromosome 10/17 translocation (4). The rearrangements result in constitutive activation of RET, which is phosphorylated on tyrosine and translocated from the membrane to the cytoplasm (13).

The prevalence of the RET/PTC rearrangements varies widely in different studies (14, 15, 16), but is generally higher in PTCs from younger patients (17, 18, 19) and in patients exposed to radiation before the development of their PTC (16, 17, 20, 21). RET/PTC3 is more prevalent than RET/PTC1 in the Chernobyl-associated childhood PTCs (17, 22). A recent study has demonstrated RET/PTCs, predominantly RET/PTC1, in 84% of PTCs and also in 45% of thyroid follicular adenomas from French patients previously exposed to external radiation (not from Chernobyl) (16). Before this, RET/PTC was generally thought to be unique to PTC. Furthermore, some of the apparent variation in RET/PTC prevalence may be due to methodology. Some investigators have inferred RET activation by the presence of RET tyrosine kinase (TK) domain messenger ribonucleic acid (mRNA) in PTCs (18). Others examine for the presence of RET/PTC directly by RT-PCR of the chimeric RNA (17, 22).

It has been suggested that the presence of RET/PTC in a tumor may predict its clinical behavior (14, 15, 23, 24), but this requires further clarification.

We examined prospectively the prevalence of specific RET/PTC sequence rearrangements and RET TK domain sequence expression by RT-PCR in 50 PTCs from adult patients. We correlated the genetic findings with any history of radiation exposure and with the MACIS clinical score (25) as well as with individual clinical parameters to determine whether the presence or absence of RET/PTC expression was associated with clinical outcome in patients with PTC.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

PTCs were collected prospectively, frozen in liquid nitrogen at the time of thyroidectomy, and stored subsequently at -70 C. The patients were 50 adults in whom the diagnosis of PTC was confirmed with formal histology of adjacent tissue. Clinical features in these patients and any history of prior exposure to ionizing radiation were noted and recorded in a database. All patients gave informed consent.

The MACIS clinical score and clinical prognostic parameters

The patients were divided into two genetic groups, those with a RET rearrangement in their tumor vs. those without, and into two clinical groups, those with MACIS scores less than 7 (where the 20-yr cause-specific survival is 89% or greater) and those with MACIS scores of 7 or more (where the 20-yr survival is 56% or less) (25). Two-tailed Fisher’s exact test was used to analyze any association between the genetic and clinical groups. In addition, any association between either of the genetic groups and individual clinical parameters was analyzed. The Mann-Whitney test was used to correlate age and tumor size with genetic findings, and Fisher’s exact test was used to correlate local invasion, lymph node involvement, and distant metastases with genetic findings.

RT-PCR

RNA was extracted from the tumors (and from the control cell line, TPC-1), using Tri-Reagent (Molecular Research Center, Inc.). RT-PCR was performed using two different pairs of primers specific for RET/PTC1 and two different combinations of primers for RET/PTC2 and RET/PTC3 (see Table 2Go). One microgram of total RNA from each tumor was reverse transcribed in a volume of 30 µL containing 10 mM Tris-chloride, 50 mM potassium chloride, 2.5 mM Mg chloride, deoxy-NTPs (Boehringer Mannheim, Indianapolis, IN), 0.7 pmol reverse primer, 33 mM dithiothreitol (Life Technologies, Grand Island, NY), 12 U RNasin, (Promega Corp., Madison, WI), and 40 U Superscript reverse transcriptase (Life Technologies). The reaction was performed at 42 C for 30 min, denatured at 95 C for 5 min, and placed on ice. The volume was then increased to 50 µL by the addition of 0.7 pmol forward primer and 2.5 U Taq polymerase (Perkin-Elmer Corp., Norwalk, CT). Amplification of the complementary DNA was carried out with 40 cycles of denaturation at 94 C for 30 s, annealing at 55 to 63 C for 1 min, and extension at 72 C for 1 min. RNA from the TPC-1 cell line (containing the RET/PTC1 rearrangement) along with cloned vectors containing RET/PTC2 and RET/PTC3 rearranged genes were used as positive controls and were all obtained from Dr. S. Jhiang (Columbus, OH). RT-PCR using primers for RET TK domain (exons 12–13 and exons 15–17) was performed on all samples, as was RT-PCR for RET extracellular (exon 2 and exons 7 and 8) and transmembrane domain (exons 11–13). All samples were screened for calcitonin expression by RT-PCR to help exclude the presence of C cells that express RET. RNA integrity was confirmed in all samples with RT-PCR for ß2-microglobulin. Two negative controls were included in every reaction (Fig. 1Go).


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  		Table 2. RTPCR primers

 


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  		Figure 1. A, RT-PCR products for RET/PTC1 (primers 11 and 8; Table 2Go). The expected product size is 223 bp. Lane 3 is the positive control, the PTC cell line TPC1, and lanes 4–7 show the four tumors that demonstrated RET/PTC 1. Lanes 1 and 2 are tumors that did not contain RET/PTC 1. Lanes C1 and C2 are negative controls with no RNA and no RT, respectively. The marker lane M contains 500 ng pUC digested with HpaII (Bresatec). B, Sequence of the RET/PTC1 PCR product from the PTC in lane 4 of A, confirming the chimeric sequence H4/RET from bottom to top. Primer 11 (Table 2Go), which binds in gene H4, was used for sequencing across the H4/RET junction.

 
Sequencing

All samples positive for a RET rearrangement and all RET TK-positive samples were sequenced using the dideoxy-DNA T7 Sequenase kit (U.S. Biochemical Corp.-Amersham).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patients

A summary of the clinical data for the 50 patients is given in Table 1Go. Three of these 50 patients (aged 32, 35, and 42 yr) had a history of exposure to significant external beam head and neck irradiation at less than 15 yr of age before the diagnosis of PTC, for acute leukemia, for a cerebral tumor, and for cystic acne, respectively.


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  		Table 1. Clinical data

 
RET/PTC analysis

RT-PCR demonstrated RET/PTC1 in 4 of 50 tumors (8%; Fig. 1AGo). This finding was confirmed by sequencing the PCR product, including the segment encompassing the H4/RET junction (Fig. 1BGo). Two of the 4 patients whose tumors exhibited RET/PTC1 were exposed to radiation in childhood or adolescence. The prevalence of RET/PTC1 positivity in the subgroup of 3 radiation-exposed patients was, thus, 2 of 3 (66.6%), which is significantly higher than the prevalence in nonirradiated patients of 2 of 47 (4.2%; P = 0.014).

No tumors contained the RET/PTC2 or RET/PTC3 rearrangements (Fig. 2Go). Different primer sets for each rearrangement gave concordant results.



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  		Figure 2. RT-PCR products for RET/PTC2 in lanes 1–4 (primers 12 and 8; Table 2Go) and RET/PTC3 in lanes 5–7 (primers 13 and 8; Table 2Go). The expected product sizes are 265 bp for RETPTC2, shown by the positive control in lane 1, and 332 bp for RET/PTC 3, shown by the positive control in lane 5. None of the PTCs demonstrated the RET/PTC2 or RET/PTC3 rearrangements, and negative controls are designated C1 and C2.

 
RET TK domain mRNA detected by RT-PCR using primers in exons 12 and 13 of RET was present in 35 of 50 (70%) of the PTCs (Fig. 3AGo), including all 4 of the tumors in which the RET/PTC1 rearrangement was demonstrated. In contrast, RT-PCR with primers in RET exons 15 and 17 was positive in 12 of 50 (24%) cases (Fig. 3BGo). The specificity of the RET TK PCR products was confirmed in all positive cases by sequencing.



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  		Figure 3. A, RT-PCR products for RET tyrosine kinase exons 12 and 13 (primers 6 and 9, respectively; Table 2Go). The expected product size is 235 bp, shown by the positive control in lane 6, which used RNA extracted from a medullary thyroid carcinoma (MTC). Tumors in lanes 2, 3, 4, 7, and 8 were positive for RET TK expression (exons 12/13), whereas a PTC in lane 5 and a normal thyroid in lane 1 were negative. B, RT-PCR products for RET TK exons 15 and 17 (primers 14 and 15, respectively; Table 2Go). The expected product size of 155 bp is shown by the positive control, MTC, in lane 3. Lanes 2, 4, 5, 6, and 8 are tumors positive for RET TK expression (exons 15 and 17), and lanes 1 and 7 are PTCs that are negative.

 
Possible reasons for the discordance between the expression of RET/PTC1 mRNA and RET TK mRNA, including the presence of C cells in the tumor specimen, were examined. Calcitonin mRNA was not detected by RT-PCR in any of the tumor specimens (Fig. 4Go). Furthermore, no tumors demonstrated RET mRNA expression using a primer pair amplifying RET exons 11–13 or using primers in the RET extracellular domain in exon 2 and exons 7 and 8 (Fig. 5Go). Thus, RT-PCR in no case detected endogenous RET extracellular domain mRNA expression despite the high prevalence of RET TK mRNA expression.



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  		Figure 4. RT-PCR products for calcitonin expression (primers 16 and 17; Table 2Go). The expected product size of 401 bp is shown by the positive control, medullary thyroid carcinoma (MTC), in lane 2. Lane 1 contains RNA from normal thyroid, lanes 3–6 are PTCs that do not demonstrate calcitonin expression, and lane C1 is a negative control.

 


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  		Figure 5. RT-PCR products for RET extracellular and transmembrane domains. Positive controls are shown in lanes 1, 4, and 7, with expected product sizes of 104, 184, and 328 bp, respectively: each used RNA from a medullary thyroid carcinoma (MTC) as template. RET exon 2 is shown in lanes 1–3 (primers 1 and 2; Table 2Go). RET exons 7 and 8 are shown in lanes 4–6 (primers 3 and 4; Table 2Go). RT-PCR products for RET exons 11–13 (primers 5 and 9; Table 2Go) are shown in lanes 7–9.

 
Clinical analysis

There was no significant difference between the two clinical patient groups (MACIS score, <7 vs. >=7) with respect to the presence or absence of RET/PTC in the patient’s tumor or indeed with respect to the presence or absence of RET TK domain expression in the tumor, as assessed by RT-PCR using either the exon 12/13 or the exon 15/17 primers. Furthermore, there was no association between any individual clinical parameters, including age, tumor size, local invasion, lymph node involvement, or distant metastases, and the presence or absence of RET/PTC.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The prevalence of RET/PTC rearrangements in PTC series from around the world varies widely from approximately 3% (26) to 85% (16) and may be influenced by a number of factors. Exposure to radiation and younger age of onset of PTC are each associated independently with a higher prevalence (17, 19, 22), and studies of PTC from the Chernobyl area describe a RET/PTC prevalence of the order of 70% (20, 21, 22).

In our series, RET/PTC rearrangements were found in only 4 of 50 (8%) adult PTCs, and 2 of the RET/PTC positive tumors were from the subgroup of 3 radiation-exposed patients. RET/PTC3 is more prevalent than RET/PTC1 in Chernobyl-associated PTCs (17, 22), but not in other radiation-associated PTC series (16). In our study, all rearrangements were RET/PTC1, and in the recent French study of radiation-exposed patients with PTCs not associated with Chernobyl, the rearrangements were predominantly RET/PTC1. There are very few such studies of RET/PTC in PTCs of adults with prior radiation exposure not linked to Chernobyl.

RET/PTC analysis is most commonly performed using RT-PCR. A previous study used the fact that RET mRNA is not normally expressed in thyroid follicular cells or PTCs, and the ability to amplify RET TK domain in PTCs was taken as an indication of RET activation (18). One must be confident that there is no C cell contamination from normal thyroid or low level "normal" RET expression in PTC to draw this conclusion.

There was a large and unexpected discrepancy between the numbers of tumors in which the RET TK exon 12/13 domain was amplified (35 of 50) and those that contained definite RET/PTC rearrangements (4 of 50). There was a smaller, but not insignificant, discrepancy between those in which the RET TK exon 15/17 domain was amplified (12 of 50) and those that contained a RET/PTC rearrangement (4 of 50). Nikiforov et al. have also reported this phenomenon, but to a lesser extent (17).

These discrepancies do not appear to be due to C cell contamination of tumor samples, as calcitonin mRNA could not be amplified from any tumor sample. Furthermore, neither the RET mRNA extracellular domain nor the RET transmembrane domain could be amplified in the samples that were TK positive. Possible explanations for this are the amplification of other TKs with high homology to RET or the existence of other as yet unidentified RET rearrangements. Primers used for RT-PCR of both RET TK domains were highly specific for RET, and sequencing of the TK-positive tumors showed the TK domain to be RET TK in all cases. These observations make the explanation of cross-homology with other TKs unlikely. Nevertheless, it seems most likely that low level RET expression accounts for the TK expression. Preliminary analysis of other non-PTC tissues, such as follicular adenomas, suggests that RET TK expression is common when using RT-PCR with either TK primer set (data not shown). This does not, however, explain why expression of the RET exon 12/13 TK domain is more frequent than expression of the exon 15/17 TK domain or indeed of the RET extracellular domain. It is possible that the amplification reaction efficiencies differ, so that low levels of expression may be detected by one set of primers but not by another.

Low sample availability precluded the use of Southern analysis to detect genomic rearrangements and also prevented further analysis of the upstream sequence of the TK-positive tumors by other techniques.

There is much interest in finding genetic markers that predict the behavior of thyroid tumors, as histological features alone may fail to do so. It has been suggested that the presence of RET/PTC may be associated with a greater likelihood of metastatic spread and poorer prognosis (23). It has also been suggested, however, that RET/PTC positivity correlates with smaller tumor size and early lymph node spread but lower metastatic potential (14, 24). The small number of tumors with RET/PTC and the short follow-up period in such studies make statistically significant conclusions on long term prognosis difficult. In our study, there was no significant difference in the MACIS scores or in individual clinical parameters in those patients with RET/PTC rearrangements in their tumors vs. those without. There were, however, only four patients with tumors containing RET/PTC. Prospective collaborative studies will need to be performed to determine whether specific genetic changes such as RET/PTC have prognostic significance.

RET/PTC rearrangements are relatively uncommon in this study of adult PTC, but are more prevalent in the subgroup of patients exposed to radiation in childhood. RET/PTC1 is the most common form of RET/PTC in PTCs from adults with a history of external beam irradiation in childhood. This contrasts with PTCs associated with the Chernobyl nuclear accident, where RET/PTC3 is more common.

RET TK domain mRNA expression detected by RT-PCR is a frequent finding in PTCs and cannot be used to infer the presence of specific RET/PTC rearrangements, or indeed of RET activation.


   Acknowledgments
 
The authors thank Dr. Sissy Jhiang (Columbus, OH) for providing the TPC1 cell line and the RET/PTC2 and RET/PTC3 positive controls. Mrs. Diana Benn is thanked for her help collecting fresh tumor samples, as are the many clinicians whose patients were referred for thyroidectomy.


   Footnotes
 
1 This work was supported by the National Health and Medical Research Council of Australia (to D.L.L.) and the Swedish Cancer Foundation (to J.Z.). Back

Received April 16, 1998.

Revised June 15, 1998.

Accepted July 2, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Santoro M, Carlomagno F, Hay ID, et al. 1992 Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest. 89:1517–1522.
  2. Santoro M, Sabino N, Ishizaka Y, et al. 1993 Involvement of RET oncogene in human tumors: specificity of RET activation to thyroid tumors. Br J Cancer. 68:460–464.
  3. Grieco M, Santoro M, Berlingieri MT, et al. 1990 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.[CrossRef][Medline]
  4. Bongarzone I, Monzini N, Borrello MG, et al. 1993 Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RIa of cyclic AMP-dependent protein kinase A. Mol Cell Biol. 13:358–366.[Abstract/Free Full Text]
  5. Jhiang SM, Smanik PA, Mazzaferri EL. 1994 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.[CrossRef][Medline]
  6. Bongarzone I, Butti MG, Coronelli S, et al. 1994 Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. Cancer Res. 54:2979–2985.[Abstract/Free Full Text]
  7. Santoro M, Dathan NA, Berlingieri MT, et al. 1994 Molecular characterization of RET/PTC3; a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. Oncogene. 9:509–516.[Medline]
  8. Fugazzola L, Pierotti MA, Vigano E, Pacini F, Vorontsova TV, Bongarzone I. 1996 Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer. Oncogene. 13:1093–1097.[Medline]
  9. Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. 1996 A new form of RET rearrangement in thyroid carcinomas of children after the Chernobyl reactor accident. Oncogene. 13:1099–1102.[Medline]
  10. Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM. 1998 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.[Abstract/Free Full Text]
  11. Pierotti MA, Santoro M, Jenkins RB, et al. 1992 Characterisation of an inversion of 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.[Abstract/Free Full Text]
  12. Minoletti F, Butti MG, Coronelli S, et al. 1994 The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2. Genes Chromosomes Cancer. 11:51–57.[Medline]
  13. Lanzi C, Borrello MG, Bongarzone I, et al. 1992 Identification of the product of two oncogenic rearranged forms of the RET proto-oncogene in papillary thyroid carcinomas. Oncogene. 7:2189–2194.[Medline]
  14. Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa SL. 1996 ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? J Clin Endocrinol Metab. 81: 3360–3365.
  15. Jhiang SM, Caruso DR, Gilmore E, et al. 1992 Detection of the PTC/retTPC oncogene in human thyroid cancers. Oncogene. 7:1331–1337.[Medline]
  16. Bounacer A, Wicker R, Caillou B, et al. 1997 High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene. 15:1263–1273.[CrossRef][Medline]
  17. Nikiforov YE, Rowland JM, Bove KE, Monforte Munoz H, Fagin JA. 1997 Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 57:1690–1694.[Abstract/Free Full Text]
  18. Williams GH, Rooney S, Thomas GA, Cummins G, Williams ED. 1996 Ret activation in adult and childhood papillary thyroid carcinoma using a reverse transcriptase-n-polymerase chain reaction approach on archival-nested material. Br J Cancer. 74:585–589.[Medline]
  19. Bongarzone I, Fugazzola L, Vigneri P, et al. 1996 Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma. J Clin Endocrinol Metab. 81:2006–2009.[Abstract]
  20. Fugazzola L, Pilotti S, Pinchera A, et al. 1995 Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res. 55:5617–5620.[Abstract/Free Full Text]
  21. Ito T, Seyama T, Iwamoto KS, et al. 1994 Activated RET oncogene in thyroid cancers of children from areas contaminated by Chernobyl accident. Lancet. 344:259.
  22. Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. 1995 High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. Oncogene. 11:2459–2467.[Medline]
  23. Jhiang SM, Mazzaferri EL. 1994 The ret/PTC oncogene in papillary thyroid carcinoma. J Lab Clin Med. 123:331–337.[Medline]
  24. Mayr B, Goretzki P, Ruschoff J, Dralle H. 1997 Ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential [Letter]? J Clin Endocrinol Metab. 82:1306–1307.[Free Full Text]
  25. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. 1993 Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery. 114:1050–1057.[Medline]
  26. Zou M, Shi Y, Farid NR. 1994 Low rate of ret proto-oncogene activation (PTC/retTPC) in papillary thyroid carcinomas from Saudi Arabia. Cancer. 73:176–180.[CrossRef][Medline]



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