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[Cancer Research 60, 2786-2789, June 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Translocation t(10;14)(q11.2;q22.1) Fusing the Kinectin to the RET Gene Creates a Novel Rearranged Form (PTC8) of the RET Proto-Oncogene in Radiation-induced Childhood Papillary Thyroid Carcinoma1

Konstadinos Salassidis, Jochen Bruch, Horst Zitzelsberger, Edmund Lengfelder, Albrecht M. Kellerer and Manfred Bauchinger2

Institute of Radiation Biology, Ludwig Maximilians University, D-80336 München [K. S., H. Z., E. L., A. M. K.], and Institute of Radiobiology, GSF-National Research Center for Environment and Health, D-85764 Neuherberg [K. S., J. B., H. Z., M. B.], Germany


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Evaluation of 20 cases of radiation-induced childhood papillary thyroid carcinoma using fluorescence in situ hybridization demonstrated the presence of clonal translocations affecting the RET locus. Semiquantitative reverse transcription-PCR indicated overexpression of the RET tyrosine kinase (TK) domain in four cases. In two cases, the RET rearrangements PTC6 and PTC7 were identified and assigned to balanced translocations t(7;10)(q32;q11.2) and t(1;10)(p13;q11.2), respectively. In one case with a balanced translocation t(10;14)(q11.2;q22.1), 5' rapid amplification of cDNA ends revealed a novel type of RET oncogenic activation (PTC8), arising from a fusion of the 5' part of the kinectin (KTN1) gene to the TK domain of the RET gene. The presence of coiled-coil domains in the resulting ktn1/ret fusion protein suggests ligand-independent dimerization and thus constitutive activation of the ret TK domain.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Thus far, several different forms of RET proto-oncogene activation have been reported in PTCs3 from children in areas of Belarus exposed to fallout from the Chernobyl reactor accident. In all of these cases, the TK domain of the RET proto-oncogene is fused to 5' end sequences of different genes constitutively expressed in follicular cells of the thyroid. As a consequence, active chimeric forms of the RET proto-oncogene occur, which are responsible for the generation of fusion proteins exhibiting coiled-coil domains that allow dimerization and thus ligand-independent activation of the cytoplasmic ret TK domain (1, 2, 3, 4, 5, 6, 7, 8) . The chromosomal mechanisms generating the oncogenic versions of PTC1, PTC3, and PTC4 have been identified as paracentric inversions on 10q with the activating genes H4 and ELE1 located at 10q21 and 10q11.2, respectively (7 , 9) . The PTC2 oncogenic form is caused by a balanced translocation t(10;17)(q11.2;q23) fusing the TK domain of the RET proto-oncogene with the regulatory subunit RI{alpha} of the c-AMP-dependent protein kinase (9) . The PTC5 form is reported to be the result of a chromosomal rearrangement fusing the 5' end of a gene designated RFG5 with the RET TK domain (3) . In the PTC6 rearrangement, the RET TK domain is fused to the hTIF1 gene (4) . In the PTC7 activating form, the RET TK domain is fused to a hTIF1-related gene designated as RFG7 (4) . Recently, a novel rearrangement was found in a sporadic PTC in which the RET gene was joined to the ELKS gene because of a chromosomal translocation t(10;12)(q11;p13) (10) .

In the present study, we have re-evaluated 20 radiation-induced childhood PTCs from a previous investigation (8) that were negative for PTC1–4 types of RET rearrangements. These cases were screened for additional RET rearrangements in interphase and metaphase cells using FISH with RET-specific YAC DNA probes (11) . In one case, a novel oncogenic RET rearrangement could be identified and designated PTC8. It is caused by a balanced translocation t(10;14)(q11.2;q22.1) fusing the RET TK domain to the KTN1 gene (12 , 13) . In two additional cases, the recently described RET rearrangements PTC6 and PTC7 were detected and could be assigned to balanced translocations t(7;10)(q32;q11.2) and t(1;10)(p13;q11.2), respectively.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Tumor Specimens.
Thyroid tumor tissues were obtained from Belarussian children who underwent surgery at the Department of Surgery, Medical High School of Minsk. All patients lived in areas contaminated by radioiodine from the Chernobyl reactor accident (8) .

Tissue Culture and Chromosome Preparation.
Primary cell culture and chromosome preparation were performed as described previously (14) . In brief, disaggregated tissues were seeded directly onto glass slides, and chromosome preparations were carried out after an in vitro culture of cells for 8–21 days. The epithelial nature of cultured cells was assessed by immunocytochemical staining of anticytokeratin (AE1/AE3; Boehringer Mannheim). For FISH analysis, slides were aged for 7 days at 37°C and stored at -20°C under nitrogen atmosphere until use.

FISH with RET-specific YAC DNA Probes.
The YAC DNA probes used in the present study were selected as described previously (11) . The YAC clones 313F4 and 214H10 map proximal to and include the RET gene locus, whereas clone 55A10 contains DNA sequences distal to RET. Total yeast DNA was extracted according to standard procedures and was labeled with digoxigenin-11-dUTP (55A10) or biotin-16-dUTP (214H10 and 313F4) by nick translation. Hybridization and detection of fluorescence signals was performed as described previously (15) .The cells were analyzed with a Zeiss Axioplan 2 fluorescence microscope equipped with filter sets for 4',6-diamidino-2phenylindole, FITC, and tetramethylrhodamine isothiocyanate. For each investigated case, at least 100 images (interphase cells and metaphase spreads) were acquired using the ISIS3/V. 3.04 software (Metasystems, Altlussheim). The hybridization efficiency of the selected probe combination to the RET locus was tested on cultivated normal thyroid epithelial cells. Cells from a short-term primary culture derived from a thyroid tumor with a PTC1 rearrangement, previously proven by RT-PCR and direct sequencing (8) , were used to evaluate the suitability of this set of probes to detect RET rearrangements in interphase nuclei and metaphase spreads.

mRNA Isolation, RT-PCR, and Semiquantitative RT-PCR.
Poly(A)+ mRNA was extracted from thyroid tumors using a Micro-Fast Track mRNA Isolation kit (Invitrogen, Leek, the Netherlands). Reverse transcription was performed with a cDNA Cycle kit (Invitrogen), and RT-PCR was carried out using specific primers (PTC5aV/retc2, PTC6bV1/retc5, and PTC7V/retc2; Table 1Citation ) for the recently detected RET rearrangements PTC5–7. In cases that failed to show expression of known ret/PTC chimeric transcripts, semiquantitative RT-PCR was performed as described (1) using primers tm1, retc1, and FlTC-labeled retc2 (Table 1)Citation . The generated PCR products TM/TK (462 bp) and TK (235 bp) were semiquantitatively analyzed on an automatic sequencer (ALF; Pharmacia).


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  		Table 1 Position of selected primers

 
5' RACE.
Rapid amplification of unknown 5' cDNA ends was performed using the 5' RACE system (Life Technologies, Inc.) according to the manufacturer’s recommendations. In brief, first-strand cDNA was synthesized from poly(A)+ mRNA using a RET-specific reverse primer (retc2; Table 1Citation ). A homopolymeric tail was then added to the 3'-end of the resulting cDNA using terminal deoxynucleotidyl transferase and dCTP. PCR amplifications were accomplished using the provided forward primers and RET-specific reverse primers RETSP2 and RETSP3 (Table 1)Citation containing uracil DNA glycosylase cloning sequences. PCR products were cloned into the pAMP1 vector using the CLONEAMP uracil DNA glycosylase cloning method (Life Technologies, Inc.). SP6 and T7 promoter primers were used for sequencing of selected clones containing the unknown 5'-end of chimeric cDNA representing novel RET oncogenic rearrangements.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Validation of YAC Probes.
FISH on cultivated normal thyroid epithelial cells with unrearranged RET loci revealed two yellow signals or tightly colocalized red and green signals in metaphase spreads (Fig. 1Citation A) and in interphase nuclei (Fig. 1BCitation ). In metaphase (Fig. 1CCitation ) and interphase (Fig. 1DCitation ) cells from a thyroid tumor with a previously proven PTC1 rearrangement, the expected paracentric inversion, could be clearly demonstrated by the presence of colocalized signals on normal chromosome 10 but split red and green signals on the affected chromosome 10.



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  		Fig. 1. FISH with RET-specific YAC DNA probes. Normal thyroid cells with unrearranged RET locus in metaphase spreads (A) and interphase nuclei (B) showing tightly colocalized red and green signals. Metaphase (C) and interphase (D) cells from a papillary thyroid carcinoma with a previously proven PTC1 interchromosomal rearrangement showing colocalized red and green signals on normal chromosome 10 and split red and green signals on the affected chromosome 10. Metaphase (E) and interphase (F) cells from papillary thyroid carcinoma S284 with a balanced translocation affecting the RET locus showing colocalized red and green signals on normal chromosome 10 and split red and green signals on two derivative chromosomes der(1)t(1;10) and der(10)t(1;10), respectively. Note the larger physical distance between split signals for the interchromosomal compared with the intrachromosomal rearrangement.

 
Detection of Novel RET Rearrangements.
Twenty PTC1–4 negative cases from our previous RT-PCR study (8) for which primary cell cultures were available were re-evaluated for novel RET rearrangements using RET-specific YAC DNA probes. The molecular-cytogenetic analysis in interphase nuclei revealed in each of four cases (S253, S271, S284, and S299) colocalized signals accompanied by split signals. The larger physical distances compared with those observed for the intrachromosomal PTC1 paracentric inversion were regarded as an indication for the existence of interchromosomal rearrangements affecting the RET locus (Fig. 1FCitation ). Actually, translocations could be confirmed on metaphase spreads (Fig. 1ECitation ) and cytogenetically characterized in detail using the 4',6-diamidino-2-phenylindole banding pattern in combination with FISH [S253, t(10;15)(q11.2;q22); S271, t(10;14)(q11.2;q22.1); S284, t(1;10)(p13;q11.2); and S299, t(7;10)(q32;q11.2)]. RT-PCR using specific primers (Table 1)Citation for PTC5–7 rearrangements and subsequent direct sequencing demonstrated in cases S284 and S299 the presence of PTC7 and PTC6 transcripts, respectively (Fig. 2Citation A), whereas in cases S253 and S271, none of these recently identified RET rearrangements were found. Interestingly, the balanced translocation t(1;10)(p13;q11.2) generating the PTC7 rearrangement has been reported previously in a sporadic papillary thyroid carcinoma (16) . In S253 and S271, semiquantitative RT-PCR analysis of the simultaneously generated PCR fragments TM/TK and TK demonstrated a clear quantitative shift toward the TK fragment (Fig. 2CCitation ). This strongly indicates that the respective balanced translocations represent novel types of RET oncogenic rearrangements.



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  		Fig. 2. A, identification of HTIF1/RET (Lane 1) and RFG7/RET (Lane 2) PCR fragments of the expected size (256/358 bp and 388 bp, respectively) demonstrating the presence of PTC6 and PTC7 rearrangements in tumor samples S299 and S284, respectively. Lane M, molecular size standard pUC Mix Marker. B, RT-PCR analysis using primers KTN1F and RETSP3 demonstrated the expression of chimeric KTN1/RET transcripts (331 bp) in tumor sample S271 (Lane 1) but not in the corresponding nontumorous material (Lane 2). Expression of the KTN1 gene in normal human thyroid tissue is confirmed by the amplification of a 494-bp cDNA fragment using KTN1-specific primers (Lane 3). Lane M, molecular size standard pUC Mix Marker. C, semiquantitative RT-PCR and quantification of the relative amounts of the simultaneously generated PCR fragments TM/TK and TK. The clear quantitative shift toward the TK fragment is indicative for the presence of novel RET rearrangements in tumors S253 and S271, related to the detected balanced translocations.

 
Identification of the RET Fused Gene.
The 5' RACE technique was performed to amplify the unknown 5' ends of rearranged RET cDNA from tumor samples S253 and S271. The resulting cDNA fragments were cloned and sequenced. Comparison of the obtained sequences with the EMBL database using the BLAST program showed that in case S271, a 5' unrelated sequence was fused to the RET cDNA sequence. This sequence was identical to the 5' part of the KTN1 gene (Ref. 17 ; Fig. 3Citation ) which has been mapped by FISH to chromosomal band 14q22.1 (18) . To our knowledge, this is the first report on the involvement of KTN1 in the development of human tumors. In case S253, studies are in progress to determine the respective ret-fused gene.



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  		Fig. 3. Sequence analysis of the novel PTC8 rearrangement detected in case S271. Arrow, fusion point of the genes KTN1 and RET.

 
Confirmation of 5' RACE Results.
To confirm the expression of KTN1/RET fusion mRNA in tumor S271, we performed RT-PCR with appropriate primers (KTN1F/RETSP3; Table 1Citation ) that generate a PCR fragment spanning the fusion region. We successfully amplified the expected PCR product KTN1/RET (331 bp) if cDNA from this tumor was used as a template but not if cDNA from the corresponding nontumorous material was used (Fig. 2BCitation ). Finally, the use of KTN1-specific primers (KTN1F/KTN1R; Table 1Citation ) resulted in amplification of the expected PCR fragment (494 bp) in the corresponding nontumorous material (Fig. 2BCitation ), demonstrating constitutive expression of KTN1 in thyroid epithelium. The authenticity of RT-PCR products was confirmed by direct sequencing.

Putative Role of the KTN1/RET Fusion Protein in Development of PTCs.
Kinectin is a cytoplasmic-oriented vesicle membraneanchored protein that interacts with the molecular motor kinesin, promoting the kinesin-dependent organelle movement along microtubules. The predicted open reading frame encodes for a protein of 156 kDa molecular mass, which contains an NH2-terminal transmembrane domain and two COOH-terminal leucine zipper motifs (12) . Analysis of the amino acid sequence predicted the formation of {alpha} helical domains within a large region between residues 327 and 1362 (12) . The presence of heptad repeats (13 , 17) in the helical domain regions is highly indicative for the formation of coiled-coil structures, suggesting that kinectin can form dimers. The dimerization capacity of kinectin is further supported by the presence of the above-mentioned leucine zipper motifs located between amino acid residues 934–962 (12) .

The comparison of the kinectin amino acid sequence (12) with the predicted ktn1/ret fusion protein sequence revealed that amino acid 963 of kinectin was fused to amino acid 713 of ret in tumor S271. The COOH-terminal part of ret with the functional TK domain was juxtaposed to the leucine zipper motifs of the NH2-terminal part of kinectin. Because KTN1 is expressed in the thyroid and its product can mediate dimerization via coiled-coil domains, we concluded that the 5' part of KTN1 fused to the RET TK domain is responsible for ectopic expression and ligand-independent activation of the ret TK domain, leading to oncogenic transformation of thyroid cells.

The proposed mechanism of constitutive activation of the ret TK domain in the novel ktn1/ret fusion protein is in accordance with findings demonstrating activation of rearranged ret oncoproteins, i.e., ligand-independent phosphorylation of tyrosine residues, resulting from RET rearrangements PTC1–PTC7 as well as from ELKS/RET. Similar to these rearrangements, the ret-fused gene KTN1 is expressed in various tissues (17) and shares with all thus-far-identified ret-fused genes (H4, RIa, ELE, RFG5, HTIF, RFG7, and ELKS) the presence of nucleotide sequences coding for proteins with an extremely high probability of forming coiled-coil domains, thus allowing constitutive dimerization of the ret TK domain.


   Acknowledgments
 
We are grateful to S. Kern, A. Schreier, K. Peters, and S. Schulte-Overberg for excellent technical assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 The work was supported in part by the European Commission Grant F14P CT95 0008. Back

2 To whom requests for reprints should be addressed, at Institute für Strahlenbiologie, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, D-85758 Oberschleissheim, Germany. Phone: 49-89-31872871; Fax: 49-89-31872873; E-mail: Bauchinger{at}gsf.de Back

3 The abbreviations used are: PTC, papillary thyroid carcinoma; YAC, yeast artificial chromosome; TK, tyrosine kinase; FISH, fluorescence in situ hybridization; RT-PCR, reverse transcription-PCR; RACE, rapid amplification of 5' cDNA ends. Back

Received 1/20/00. Accepted 4/18/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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