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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1629-1632
Copyright © 1998 by The Endocrine Society

Original Studies

High Frequency of Rearrangement of the RET Protooncogene (RET/PTC) in Chinese Papillary Thyroid Carcinomas1

Chen-Hsen Lee, Li-Sung Hsu, Chin-Wen Chi, Gen-Der Chen, An-Hong Yang and Jeou-Yuan Chen

Institute of Biomedical Sciences (G.-D.C., J.-Y.C.), Academia Sinica; Graduate Institute of Life Sciences (L.-S.H.), National Defense Medical Center; Departments of Surgery (C.-H.L.), Medical Research (C.-W.C.), and Pathology (A.-H.Y.), Veterans General Hospital-Taipei and National Yang-Ming University (C.-H.L., C.-W.C., A.-H.Y., J.-Y.C.), Taipei 11529, Taiwan, Republic of China

Address all correspondence and requests for reprints to: Dr. Jeou-Yuan Chen, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. E-mail: bmchen{at}ibms.sinica.edu.tw


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The activation of RET protooncogene, through chromosomal translocation, is unique to papillary thyroid carcinomas. Rearrangement of the RET kinase domain to 3 partner genes has been described, of which the RET/PTC1 is the most common. To investigate the frequency of RET rearrangement in Chinese papillary thyroid carcinomas, we have performed RT-PCR to amplify specific RET/PTC transcripts. Among the papillary thyroid carcinomas of 11 patients examined, we have identified 2 containing RET/PTC1, 3 containing RET/PTC2, and 1 containing RET/PTC3 oncogenes. Although the cause of the high frequency of RET/PTC oncogenes in Chinese papillary thyroid carcinomas is unknown, our study suggests that RET rearrangement is an important genetic lesion underlying the development of thyroid papillary carcinoma in Taiwan.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE RET protooncogene encodes a receptor tyrosine kinase whose ligands have recently been identified as glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) (1, 2, 3, 4). These ligands interact with RET via a glycosylphosphatidylinositol-linked adaptor molecule or coreceptor, GDNFR-{alpha} or NTNR-{alpha}, to form a multicomponent receptor system (2, 4). The RET protooncogene has frequently been found to be rearranged in thyroid papillary carcinomas (5). Three types of tumor-specific rearrangements, (RET/PTC1, RET/PTC2, and RET/PTC3) have been described in which the tyrosine kinase domain of c-RET fused with the 5' end sequence of H4 (D10S170 locus) (6), RI{alpha} (7), and ELE1 (8, 9, 10), respectively. Among them, RET/PTC1 is the most common form found in spontaneous papillary thyroid carcinoma, whereas RET/PTC3 is the prevailing type in post-Chernobyl thyroid cancers (11). Various forms of ELE1 and RET rearrangements have also been reported in the radiation-induced thyroid tumors (12, 13).

Wide differences in the frequency of RET rearrangement in thyroid papillary carcinomas have been reported in different populations. It is lower in Japanese and Saudi Arabian patients and higher in Italian and UK patients (9, 14, 15, 16). In this report, we have adopted the RT-PCR method to investigate the frequency of RET rearrangements in Chinese papillary thyroid tumors. Among the 11 papillary thyroid carcinomas examined, we identified 2 containing RET/PTC1, 3 containing RET/PTC2, and 1 containing RET/PTC3 oncogenes. The nucleotide sequence surrounding the fusion point of each RET/PTC chimeric transcript was further analyzed by direct sequencing of the PCR products.


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

All tumors were obtained from patients who underwent thyroidectomy from November 1995 through June 1996 at the Department of Surgery, Veterans General Hospital-Taipei, Taiwan, Republic of China. Informed consent was obtained from each patient. Biopsied thyroid samples were frozen in liquid nitrogen immediately after surgical removal. The main clinical characteristics of the patients are summarized in Table 1Go.


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  		Table 1. Clinical information of patients with papillary thyroid carcinoma

 
RNA isolation and RT-PCR

Total RNA was prepared by the guanidinium isothiocyanate method, followed by deoxyribonuclease I treatment (17). For complementary DNA (cDNA) synthesis, 10 µg total RNA was reverse transcribed by incubation for 50 min at 42 C, in the presence of 200 U of Molony murine leukemia virus-RT (SUPERSCPIPT II, GIBCO-BRL, Grand Island, NY) in 50 µL RT buffer containing 50 mmol/L Tris-HCl (pH 8.3), 75 mmol/L KCl, 3 mmol/L MgCl2, 0.1 mol/L dithiothreitol, 0.5 mmol/L deoxynucleotide triphosphate mix, and 0.5 µg of random hexamers.

PCR was carried out in a 10-µL reaction mixture containing 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 3 mmol/L MgCl2, 0.01% (wt/vol) gelatin, 2 mmol/L deoxynucleotide triphosphate, 0.1 µg/mL of each primer, 1 µL cDNA, and 2.5 U Taq DNA polymerase. The PCR reaction was performed with the thermal cycler PE9600 (Perkin Elmer, Foster City, CA), according to the following protocol: Initial denaturation, at 94 C for 5 min, was followed by 30 cycles of denaturation at 94 C for 1 min, annealing at 55 C for 1 min, and extension at 72 C for 1 min. As illustrated in Fig. 1aGo, primers ptcI (5'-AGA TAG AGC TGG AGA CCT AC-3'), ptcII (5'-AGG GAG CTT TGG AGA ACT TG-3'), and ptcIII (5'-CAT GCC AGA GCA GAA GTC A-3') were paired with the retc4 primer (5'-GAG CCG TAT TTG GCG TAC TC-3') to amplify the chimeric RET/PTC1, 2, and 3 cDNAs, respectively. PCR amplification was also performed with primers specific for c-MET (sense primer, 5'-CTA CAA CCC GAA TAC TGC CC-3'; antisense primer, 5'-AGC CTC TGG TTG TGA TGC TC-3'; GenBank Accession no. X54559), TKT (sense primer, 5'-CCA GCT GTC AGA TGA ACA GG-3'; antisense primer, 5'-GGC ATG GGT GAG TGG TAG GT-3') (18), and GAPDH (sense primer, 5'-TGG TAT CGT GGA AGG ACT CAT GAC-3'; antisense primer, 5'-ATG CCA GTG AGC TTC CCG TTC AGC-3'; GenBank Accession no. M17851) transcripts as controls.



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  		Figure 1. Detection of chimeric RET/PTC rearrangements by the RT-PCR method. a, Schematic representation of c-RET and RET/PTC oncogenes and the design of primers. The extracellular (EC), transmembrane (TM), and tyrosine kinase (TK) domains of the RET protooncogene are labeled. The RET/PTC rearrangement and fusion points (indicated by arrowheads) are diagrammed. The location of primers for the corresponding genes and the size of PCR products are indicated. b, Detection of specific RET/PTC transcripts. Tumor-derived cDNAs were subjected to PCR amplification using primers specific for RET/PTC1, RET/PTC2, and RET/PTC3 oncogenes, respectively. As controls for cDNA integrity, the cDNAs were also amplified with primers specific for c-MET and GAPDH. PCR products were analyzed on a 4% agarose gel and visualized after ethidium bromide staining. Lanes are designated with patients’ identification (ID) numbers, as described in Table 1Go. MW, 100-bp DNA ladder.

 
Sequencing analysis

PCR products were passed through Sepharose CL-6B columns and sequenced by direct incorporation of [{alpha}-35S]deoxyadenosine 5'-triphosphate, using the OmniBase DNA Cycle Sequencing Kit (Promega Corp., Madison, WI). Primer retc2 (5'-TGC AGG CCC CAT ACA ATT TG-3') was used as a sequencing primer (Fig. 1Go).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical data

The 11 thyroid tumors included in this study were histologically confirmed to be papillary carcinomas, and all were derived from female patients. The average age at surgery was 47.7 yr, with a range from 30–81 yr (Table 1Go). The average tumor size was 2.9 cm (range from 1.0–8.0 cm). None of the patients had a history of neck irradiation. At the time of diagnosis, 2 patients had extrathyroidal tumor invasion, and 5 had lymph node metastasis. Morphologically, there were no aggressive histological subtypes. No death or local recurrence has occurred during the period of follow-up.

Detection of specific RET/PTC rearrangements by PCR amplification of tumor-derived cDNAs

Among the 11 Chinese papillary tumors examined, 2 (PC4 and PC9) were positive for RET/PTC1, 3 (PC1, PC3, and PC7) were positive for RET/PTC2, and 1 (PC2) was positive for RET/PTC3 rearrangements (Fig. 1bGo). To exclude the possibility that the negative results obtained in other samples were caused by RNA degradation, poor cDNA synthesis, or poor PCR amplification, the same cDNA samples were used to amplify the c-MET, TKT (18) and GAPDH cDNA fragments, under the same condition. These cDNA fragments were successfully amplified in all samples, although PC2 and PC11 seemed to have decreased amounts of RNA prepared from the tumor samples (Fig. 1bGo, bottom panel; cMET and GAPDH data were shown).

The fusion points of RET/PTC chimeric transcripts identified in these papillary thyroid tumors were further examined by nucleotide sequencing analysis of the PCR products derived from RET/PTC chimeric transcripts. As shown in Fig. 2Go, each tumor that was positive for a rearranged RET/PTC oncogene exhibited the expected sequences at and around the fusion point, as previously described (6, 7, 10). Among them, PC9 (which contained RET/PTC1) was shown to contain a T to G transversion mutation in the H4 gene, as indicated. However, this nucleotide change is located at the wobble position of codon 99 in RET/PTC1 and does not lead to a change of amino acid sequence.



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  		Figure 2. Nucleotide sequence analysis of the amplified PCR products of RET/PTC. The patient’s ID number is listed at the top of each panel. Nucleotide sequences around the fusion points of the three different types of RET/PTC chimeric transcript (as indicated at the bottom of the panels) are shown, and the fusion point is marked by arrows. The nucleotide polymorphism of RET/PTC1 detected in tumor PC9 is marked with an asterisk.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The frequency of RET rearrangement in human papillary thyroid carcinomas varies widely from 2.5–53.5% among patient series from different geographical regions (see Table 2Go), and it has been suggested that different genetic or environmental factors are involved in determining the frequency of RET rearrangement in papillary thyroid carcinomas. However, the fact that different methods were used to detect the RET/PTC activation in tumors at different stages, or of different subtypes, also may contribute to the different frequency of RET activation. In general, RET activation can be detected by NIH/3T3 transformation assay (5, 9), Southern blot analysis (16, 19), RT-PCR (8, 15, 20, 21, 22), or in situ hybridization (23). The RT-PCR method, adopted in the present study, proved to be highly sensitive for detecting the expression of RET/PTC chimeric oncogenes in tumor samples. The RET/PTC chimeric transcripts were detected in 6 of the 11 Chinese papillary thyroid tumors. The high frequency of RET/PTC rearrangement in the papillary thyroid carcinomas of Chinese populations suggests that RET activation plays an important role in the tumorigenesis of papillary thyroid tumors in the Chinese population.


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  		Table 2. The RET/PTC activation in human papillary thyroid carcinomas

 
The power of PCR amplification is accompanied by the dilemma of the ease of cross-contamination between samples. In this study, extra precautions were taken to avoid cross-contamination among samples. In addition, all experimental procedures (including RNA preparation, reverse transcription, and PCR), were repeated twice by different laboratory personnel. The fact that a polymorphism (T to G transversion) in RET/PTC1 was found in tumor PC9 indicates that the presence of RET/PTC1 in tumor PC9 did not result from cross-contamination during the process of sample preparation and RT-PCR.

Possible correlation of RET/PTC rearrangement with clinical features in these Chinese patients was analyzed. Among the patients tested, the average age of the RET/PTC-positive patients was 43 yr, whereas the RET/PTC-negative patients’ average age was 53.4 yr. The average tumor size of the RET/PTC-positive patients was 1.9 cm, as compared with 3.8 cm for the RET/PTC-negative patients. Our observations are in accordance with the previous report by Sugg et al. (22), where examination of RET/PTC oncogene expression in 57 Canadian papillary carcinomas resulted in 3 RET/PTC-positive patients with an age range of 26–44 yr and a smaller tumor size (<1.2 cm).

The clinical implications of RET/PTC rearrangement in patients with papillary thyroid carcinoma have been controversial. Some authors have suggested that RET/PTC expression could serve as an indicator of aggressive behavior in papillary cancer, specifically for distant metastatic disease. In a series of patients studied in the United States, 50% (2 of 4) of RET/PTC-positive tumors had distant metastasis, whereas only 12% (4 of 32) of the RET/PTC-negative tumors had metastasized (19). The study on childhood papillary cancer associated with radiation exposure also reported a 100% (7 of 7) incidence of lymph node metastasis in tumors harboring RET/PTC rearrangements, compared with a 50% (2 of 4) incidence of lymph node metastasis in tumors without RET/PTC rearrangements (20). However, in our study, no histologically aggressive subtypes, including diffuse sclerosing, undifferentiated, or tall cell carcinomas, were found in tumors harboring RET/PTC rearrangement. Among the 5 patients with lymph node metastasis, 2 were RET/PTC-positive and 3 were RET/PTC-negative. Lung metastasis was later found in 1 of the RET/PTC-negative patients. It seems that a larger patient number and longer follow-up times are required to establish the relationship between the expression of RET/PTC and the clinical behavior of a tumor.

The high frequency of RET/PTC in Chinese papillary thyroid carcinomas is unlikely to be related to insufficient iodine uptake in Taiwan, because iodination of table salt has been implemented since 1967. However, it is not known whether an unknown source of radiation exposure is related. In this study, we detected the presence of RET/PTC2 oncogene in 3 patients. The high frequency of RET/PTC2 rearrangement in Chinese patients suggests that genetic and/or environmental factors may play a role in determining the type of RET/PTC rearrangement in papillary thyroid carcinomas. It is of interest that none of the 3 patients expressing RET/PTC2 displayed lymph node metastasis.


   Footnotes
 
1 This work was supported by National Science Council Grants NSC-87–2314-B-001–043 (to J.-Y.C.) and NSC-85–2331-B-075–034 (to C.-H.L.), and a Graduate Fellowship (to L.-S.H.) from Academia Sinica. Back

Received October 6, 1997.

Revised January 5, 1998.

Accepted January 22, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  8. Jhiang S, Smanik P, Mazzaferri E. 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]
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  11. Ito T, Seyama T, Iwamoto K, et al. 1994 Activated RET oncogene in thyroid cancers of children from areas contaminated by Chernobyl accident. Lancet. 344:259.
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