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Clinical Cancer Research Vol. 6, 1093-1103, March 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Pattern of Radiation-induced RET and NTRK1 Rearrangements in 191 Post-Chernobyl Papillary Thyroid Carcinomas: Biological, Phenotypic, and Clinical Implications1

Hartmut M. Rabes2, Evgenij P. Demidchik, Juri D. Sidorow, Edmund Lengfelder, Claudia Beimfohr, Dieter Hoelzel and Sabine Klugbauer

Institute of Pathology, Ludwig-Maximilians-University, D-80337 Munich, Germany [H. M. R., C. B., S. K.]; Thyroid Cancer Center, 220600 Minsk, Belarus [E. P. D., J. D. S.]; Institute of Radiation Biology Ludwig-Maximilians-University, D-80336 Munich, Germany [E. L.]; Department of Medical Informatics, Biometry and Epidemiology, University of Munich, D-81377 Munich, Germany [D. H.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Molecular genetic aberrations and the related phenotypes were investigated in 191 papillary thyroid carcinomas (PTCs) from patients exposed at young age to radioiodine released from the Chernobyl reactor. A high prevalence of RET gene rearrangements (62.3%) with a significant predominance of ELE1/RET (PTC3) over H4/RET (PTC1) rearrangements was found in PTCs of the first post-Chernobyl decade. NTRK1 rearrangements were rare (3.3%). In 3.3%, we observed novel types of RET rearrangements: GOLGA5/RET (PTC5), HTIF/RET (PTC6), RFG7/RET (PTC7), and an as yet undefined RFGX/RET. RET rearrangements, preferentially ELE1/RET, are related to rapid tumor development. At longer intervals after exposure to ionizing radiation, the prevalence of RET rearrangements declines with a shift from ELE1/RET to H4/RET, most significantly in female patients. The prevalence of specific types of rearrangements is independent of age at irradiation. A significantly higher prevalence of ELE1/RET was observed in the most heavily contaminated Oblasts, Gomel and Brest, suggesting a preferential formation of this type of rearrangement after high thyroid doses. RET rearrangement is related to aggressive growth: Rearrangement-positive PTCs were in a more advanced pT category and more frequently in the pN1 category at presentation than rearrangement-negative PTCs. ELE1/RET is related to the solid variant of PTC, H4/RET more frequently to typical papillary structures. The genotype/phenotype evaluation of post-Chernobyl PTCs reveals a characteristic spectrum of gene rearrangements that lead to typical phenotypes with important biological and clinical implications.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The thyroid gland is highly sensitive to irradiation during childhood. Development of thyroid carcinomas has been reported in children after therapeutic radiation (1, 2, 3, 4, 5) , as a consequence of irradiation after atomic bomb explosions (6, 7, 8) , or as a result of fallout from thermonuclear explosions at the Marshall Islands (9) . Summarizing seven studies on radiation exposure during childhood and thyroid carcinogenesis, Ron et al. (10) calculated an excess relative risk per unit thyroid dose of 7.7 Gy-1 with evidence for an increased risk at ~10-1 Gy. These data became more relevant during recent years when a steep increase of thyroid carcinomas was reported in children who lived in areas that were highly radiation contaminated after the Chernobyl reactor accident (11 , 12) . Huge amounts of radioactivity were released after the reactor explosion, with an estimated dose of radioactive iodine of ~1.8 x 1018 Bq (13) . A considerable portion of this radiation was recorded in Belarus (14) . In a case-control study, a strong relationship between tumor development and estimated radiation dose was reported (15) . These tumors provide an unprecedented chance to study molecular mechanisms of radiation-induced thyroid carcinogenesis: A large population of children was exposed to high thyroid doses of radioiodines during a short period of time. After a latency period of ~4 years, the first thyroid carcinomas occurred, with increasing incidence during the following years (16) . Almost exclusively, PTCs developed (17, 18, 19) that exhibited aggressive growth and early metastasis (20) .

Until recently, not much was known about genetic aberrations in childhood PTCs.3 In adults, RAS and p53 mutations have been found in papillary carcinomas. In a few thyroid tumors, mostly hyperfunctional adenomas, mutations of the GS{alpha} gene have been observed (see Ref. 21 ). Mutations of these genes do not play a role in post-Chernobyl PTCs. Analysis of 79 post-Chernobyl tumors revealed missense mutations of p53 in one case only (22, 23, 24) . RAS or GSP mutations have not been found at all (22 , 24 , 25) .

The prevalence of RET rearrangements observed in PTCs of adults differs in various geographical areas with a mean value of 15.8% (see Ref. 21 ). cRET encodes a receptor TK (26) and is involved in a stage-dependent mode (27) in the development of kidney, enteric nervous system and tissues from the neural crest, and tumors derived thereof (28) . The NTRK1 gene represents the receptor for nerve growth factor (29) . It plays an essential role in developmental processes of the nervous system. Both genes, cRET and NTRK1, undergo oncogenic activation by chromosomal rearrangements. The COOH-terminal part of RET, containing the TK domain, is fused to the NH2-terminal part of other genes. PTC1 consists of the fusion of the RET TK domain with a part of the H4 gene (30) . In PTC2, the RET TK domain is fused to the regulatory subunit RI{alpha} of the cAMP-dependent protein kinase A (31) . In PTC3, RET is connected with the NH2-terminal part of ELE1 (32 , 33) , which has recently been identified as transcription coactivator of the androgen receptor (34) .

Fusion of the NTRK1 TK domain to 5' sequences of other genes leads to oncogenic activation of NTRK1 (35) . NTRK1 rearrangements are less frequently found in PTCs than RET rearrangements. In an Italian series of 76 consecutive PTCs, 11.8% contained activated NTRK1 (36) .

RET and NTRK1 rearrangements are of minor importance in spontaneous PTCs, but the prevalence of RET rearrangements is high in post-Chernobyl PTCs. The pattern of genotype alterations and implications for phenotypic expression, tumor biology, and clinical course will be described.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tumors.
One hundred ninety-one patients between the ages of 0 and 18.3 years at the time of the Chernobyl reactor accident were included in this study. They served as a representative cohort for the incidence interval April 1993 until January 1998. Most of them lived in fallout-exposed areas of Belarus. A few had been exposed in areas adjacent to Belarus (Russia, n = 5; Ukraine, n = 2). All developed thyroid carcinomas till January 1998. All patients were thyroidectomized at the Thyroid Cancer Center in Minsk, Belarus. Patients’ data were obtained from the registry of this institution. Tumors were staged according to WHO (37) in Minsk. Immediately after thyroidectomy, small parts of the tumors and normal thyroid tissue were either incubated in cell culture medium and transported to Munich by air and then frozen in liquid nitrogen, or frozen at -20°C immediately after resection, transported in dry ice, and stored at -80°C after arrival in our department until further processing.

Histology.
Representative parts of tumor and adjacent normal thyroid tissue were fixed in 4% buffered formalin and embedded in paraffin. Sections (3 µm) were stained with H&E, and the histopathology was evaluated according to WHO (38) . Special attention was given to the variants of PTC, i.e., typical papillary, follicular, solid, and diffuse sclerosing variants. Cases were included in a specific variant group if more than two-thirds of the PTCs in the sections showed this specific variant. PTCs composed of approximately equal parts of typical papillary, follicular, and solid tumor tissue were included in the mixed variant group.

Molecular Analysis.
This study was performed in continuation of previously published experiments of our group, and all details of the methods used are given in those reports (39, 40, 41, 42, 43, 44) . mRNA was isolated from lysed tissue and reverse transcribed to obtain cDNA. A fraction was subjected first to multiplex PCR to check for the presence of any type of RET or NTRK1 rearrangement as documented previously (39 , 42) . Subsequently, cDNA was PCR-amplified using primer pairs (39, 40, 41 , 43) specific for H4/RET, ELE1/RET, RI{alpha}/RET, and the various RET-fused genes, RFG/RET, as well as primers specific for NTRK1 rearrangements (42) to establish presence or absence of the various types of gene rearrangements. All samples that showed gene rearrangements in the identification PCR were sequenced by the dideoxy method (45) either with [32P]dATP (Amersham, Braunschweig, Germany) as described previously (39) or, more recently, by the Applied Biosystems Sequencer 310 (Perkin-Elmer, Weiterstadt, Germany) according to the manufacturer’s description.

Statistical Evaluation.
To determine correlations between different variables, the {chi}2 test was used. Various types of RET and NTRK1 rearrangements were compared with age at exposure to radioactive fallout, residence in Belarus, gender, preclinical tumor latency period, TNM category, and histological tumor type. The probability of a difference between the groups was calculated. P < 0.05 was considered statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The Cohort of Tumors.
The results are based on the analysis of 191 PTCs (Table 1)Citation that developed from April 1993 until January 1998 in patients between 0 and 18.3 years of age at the time of radiation exposure after the Chernobyl reactor accident. The male-to-female ratio was 0.57, which was higher than in comparable young thyroid cancer patients from Italy and France (20) . The very high proportion of tumors in children exposed at an age of 4 years or younger (56.5%) confirms the hypothesis that at young age the thyroid gland is most sensitive to ionizing radiation (10) . The high percentage of children <=14 years at the time of diagnosis/surgery (51.8%) indicates a short tumor latency in agreement with published reports (11 , 12 , 20) . The largest fraction of tumors occurred in the most highly contaminated areas of Belarus, the Oblast Gomel in particular, where 46.6% of all tumors were observed. One-fifth of the cases developed in the Oblast Brest, the next highly contaminated region of Belarus. From the similarity to epidemiological data of post-Chernobyl PTCs (20) , it may be concluded that the 191 PTCs of this study are a representative cohort of post-Chernobyl tumors for the incidence interval from April 1993 to January 1998.


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  		Table 1 Data of 191 PTCs of patients exposed at young age to radioactive fallout after the Chernobyl reactor accident

 
High Prevalence of RET Rearrangements, Low Prevalence of NTRK1 Rearrangements in Early Post-Chernobyl PTCs of Children.
In a first smaller series of PTCs that developed prior to March 1995, we had observed a high prevalence of RET rearrangements with a predominance of ELE1/RET, PTC3 (39) . The observations were corroborated in the present analysis of 61 tumors that developed in children during the first decade after the reactor accident (21 , 46) . Of these PTCs, 62.3% showed RET rearrangements, almost two-thirds of them an ELE1/RET, PTC3 type, and approximately one-fourth an H4/RET, PTC1 type. RI{alpha}/RET, PTC2, was missing. In five tumors, we detected a fusion of RET with hitherto unknown genes: GOLGA5 (40) , HTIF (41) , RFG7 (41) , and RFGX (Table 2)Citation . NTRK1 rearrangements were rare (42) . In this series, we detected two cases only, among them one tumor showing a TPM3/NTRK1 and one tumor a TRK-T2 rearrangement.


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  		Table 2 RET and NTRK1 rearrangements in PTCs of children from Belarus thyroidectomized in Minsk during the first decade after the Chernobyl reactor accident (n = 61)

 
These findings strongly suggest that the predominating genetic aberration of radiation-induced PTCs is an oncogenic activation of the RET gene by rearrangement. The very high prevalence, never found to this extent in any other cohort of PTCs, represents a typical, if not characteristic, effect of high-dose thyroid irradiation after the Chernobyl reactor accident.

Changing Prevalence and Type of Rearrangement as a Function of Tumor Latency.
When we compared the tumors that developed during the first decade after the accident (Table 2)Citation with those that occurred later, we found a significantly higher prevalence of rearrangement-positive tumors in faster developing PTCs (P = 0.012; Table 3Citation ; Fig. 1Citation ). Among RET rearrangement-positive PTCs, tumors exhibiting ELE1/RET showed the fastest development. Sixty-three percent of the tumors exhibiting an ELE1/RET rearrangement were found up to 10 years after exposure, in contrast to H4/RET tumors, which are present in a low percentage at short latency periods but in 81% at a latency of >10 years (P < 0.001; Table 3Citation ; Fig. 1Citation ). It is evident from these data that the early high prevalence of ELE1/RET rearrangements decreases with time after the accident. At a latency longer than 10 years, H4/RET becomes the predominant molecular alteration.


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  		Table 3 Changes in the prevalence and type of RET and NTRK1 rearrangements in 191 PTCs of children after the Chernobyl reactor accident on April 26, 1986, as a function of the tumor latency period (interval between exposure and diagnosis/thyroidectomy)

 


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  		Fig. 1. Prevalence of gene rearrangements as a function of the tumor latency period. PTCs with clinical manifestation during the first 10 years (n = 61) and later than 10 years after the reactor accident (n = 130). Abscissa, PTC1 with H4/RET rearrangements; PTC3 with ELE/RET rearrangements; rearrangement-positive, all tumors in the categories PTC1, 3, 5–7, and X and with NTRK1 rearrangement; rearrangement-negative, PTCs lacking any of these types of rearrangements. Ordinate, percentages in each group. PTC1 versus PTC3, P < 0.001; RET and NTRK1 rearrangement-positive versus -negative PTCs, P = 0.012.

 
Independence of the Type of RET Rearrangement from Age at Radiation Exposure.
It has been claimed that ELE1/RET in PTCs is specific to patients of a young age (36 , 47) . Our results indicate that the age at radiation exposure lacks relation to a specific type of gene rearrangement (Table 4)Citation . The age group from 0 to 4 years at the time of irradiation included slightly more rearrangement-positive PTCs than negative tumors. This difference was not statistically significant (P = 0.7) when compared with the age group >4–8 years or when compared with the total age group older than 4 years. In the age group 0–4 years, tumors of the ELE1/RET type are slightly less frequent than H4/RET tumors. Their number is identical in the age group >4–8 years. Patients older than 8 years at irradiation exhibit more PTC1 than PTC3, but a statistically significant difference between the prevalence of H4/RET and ELE1/RET was not observed in any age group (Table 4)Citation . These results argue against the hypothesis that ELE1/RET is the preferred type of rearrangement after irradiation at young age.


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  		Table 4 Prevalence and type of RET and NTRK1 rearrangements as a function of age at radiation exposure (n = 191)

 
The ELE1/RET rearrangement, however, is connected to rapid tumor development, as documented above. When testing the prevalence of RET and NTRK1 rearrangements as a function of age at surgery, we observed no significant difference between rearrangement-positive and negative tumors. However, when we compared the prevalence of H4/RET and ELE1/RET rearrangements at the level below versus above an age of 14 years at surgery, we found a higher prevalence of ELE1/RET rearrangements in patients 14 years or younger compared with patients older than 14 years (P < 0.01; Table 5Citation ). It can be concluded that ELE1/RET is not characteristic to young age per se, but is typical for a short tumor latency (see Table 4Citation ).


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  		Table 5 Prevalence and type of RET and NTRK1 rearrangements as a function of age at tumor manifestation (diagnosis/thyroidectomy; n = 191)

 
Correlations between Gene Rearrangements and Patients’ Gender.
The male-to-female ratio of the whole cohort was 0.57. However, among the age group of 4 years and younger at the time of irradiation, the ratio of males (n = 63) to females (n = 45) was 1.40, in contrast to patients older than 4 years at irradiation, with a ratio of males (n = 24) to females (n = 59) of 0.41 (P < 0.0001). A similar relationship was found when we looked at the age at surgery: the ratio of males (n = 45) to females (n = 54) for patients 14 years or younger at the time of thyroidectomy was 0.83, in contrast to 0.35 for patients (male, n = 24; female, n = 68) older than 14 years at the time of surgery (P < 0.01). A difference between genders was evident with respect to tumor latency (Table 6)Citation . Female patients exhibited a significantly lower prevalence of gene rearrangements in later occurring PTCs (>10 years) than more rapidly developing tumors (<10 years latency; P = 0.03), in contrast to males (P > 0.2). The switch with an increasing latency period from a predominance of PTC3 to a higher prevalence of PTC1, as described before, is significant in females (P < 0.005) but not in males (P > 0.08; Table 6Citation ).


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  		Table 6 Differences between male and female PTC patients in the prevalence and type of RET and NTRK1 rearrangements as a function of the tumor latency period (n = 191)

 
Type of Molecular Alteration as a Function of Patient’s Residence at the Time of Radiation Exposure.
An uneven distribution of radioactive fallout has been described in Belarus. The Oblast Gomel was most severely contaminated (14 , 20) . Fig. 2Citation compiles the prevalence and type of RET and NRTK1 rearrangements in tumors from patients as a function of residence at the time of the reactor accident. The largest number of PTCs was found in the Oblasts Gomel and Brest. Approximately two-thirds of the children that developed PTC lived in these Oblasts during the time of the reactor accident. The remaining third was distributed over the four other Oblasts of Belarus: Minsk, Mogilew, Grodno, and Witebsk. ELE1/RET was significantly more prevalent in the Oblasts Gomel and Brest than in PTCs from other parts of Belarus (P < 0.01; Fig. 2Citation ).



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  		Fig. 2. Type of gene rearrangements in PTCs as a function of individual patients’ residence in various Oblasts of Belarus (abscissa) at the time of the Chernobyl reactor accident; other, unknown or adjacent parts of Russia or Ukraine. Ordinate, absolute number of PTCs in each region. PTC1 versus PTC3, P < 0.01.

 
These data suggest that the type of RET rearrangement differs with the children’s residences at the time of the reactor accident, most likely dependent on the different amount of radioiodine uptake. A higher dose appeared to produce more ELE1/RET rearrangements than H4/RET rearrangements.

Genotype and Tumor Stage.
RET rearrangement-positive tumors exhibited a more advanced pT category at the time of diagnosis (P < 0.01; Fig. 3Citation ) with a higher probability of lymph node metastasis than RET rearrangement-negative PTCs (pN0, rearrangement-positive, n = 8, rearrangement-negative, n = 19; pN1, rearrangement-positive, n = 91, rearrangement-negative n = 71; P = 0.02). A significant correlation existed between the more advanced pT3/T4 category and the presence of ELE1/RET rearrangements compared with H4/RET rearrangements (P < 0.05). This supports the notion that ELE1/RET rearrangements speed up progression not only compared with RET rearrangement-negative, but also with H4/RET rearrangement-positive PTCs (Fig. 3)Citation .



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  		Fig. 3. Differences in the pT category as a function of type of genetic aberration in post-Chernobyl PTCs. Abscissa, see legend for Fig. 1Citation ; ordinate, percentages in each group. PTC1 versus PTC3, P < 0.05; RET and NTRK1 rearrangement-positive versus -negative PTCs, P < 0.01.

 
Different Variants of Papillary Carcinomas.
In a histological analysis of 86 cases occurring in Belarus prior to 1991 (17) and of 84 tumors developing in 1991 and 1992 (18) , papillary carcinomas were found in 96.5% and 98.8% of all tumors, respectively. In the present study, papillary carcinomas were investigated. Histological typing according to the WHO classification (38) revealed typical papillary (30.9%; Fig. 4Citation ), follicular (37.2%; Fig. 5Citation ), and solid variants (22.0%; Fig. 6Citation ). They were classified according to the predominant structures (see "Materials and Methods"); in addition, mixed variants (6.3%) with approximately equal parts of papillary, follicular, and solid areas, and diffuse sclerosing variants (Refs. 48 , 49 ; 3.1%; Fig. 7Citation ) were observed. Irradiation induces, in principle, a single basic phenotype, the papillary carcinoma, but the prevalence of the different variants is related to specific genotypic changes as outlined below.



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  		Fig. 4. Histology of post-Chernobyl PTCs, typical papillary type, showing branching papillae with a fibrovascular core (A), covered by epithelial layers with closely packed large, pale overlapping round or ovoid ground glass nuclei of irregular shape with nuclear grooving (B); C, multiple intrapapillary psammoma bodies. Staining, H&E. Magnification: A, x100; B, x400; C, x250.

 


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  		Fig. 5. Follicular variants of post-Chernobyl PTCs showing variable shapes and sizes of colloid-containing follicles (A) with a dense irregular epithelial cell lining (B). Nuclei have ground glass appearance, devoid of nucleoli, often very densely packed and overlapping; some show grooves (C). Staining, H&E. Magnification: A, x100; B, x250; C, x400.

 


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  		Fig. 6. Solid variants of post-Chernobyl PTCs. A, large solid areas of irregular densely packed cells surrounded by thin fibrous stroma. B and C, the majority of cells have a fine-granular nucleus (B), but large populations of ground glass nuclei with thickening of the inner wall of nuclear membrane, some with nuclear grooving, dominate in other parts (C). Staining, H&E. Magnification: A, x250; B, x400; C, x400.

 


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  		Fig. 7. Diffuse sclerosing variants of post-Chernobyl PTCs, with extensive fibrosis and inflammation with scattered patches of tumor cells: A, predominant follicular structures; B, solid parts; C, papillary pattern with psammoma bodies. Staining, H&E. Magnification: A, x80; B, x100; C, x100.

 
The Genotype of RET Rearrangement and Morphological Phenotype.
Histology revealed that the molecular changes were reflected by specific morphological phenotypes (Table 7)Citation : ELE1/RET rearrangements show a clear connection to the histological type of the solid variant of PTC. This correlation was statistically highly significant (P < 0.001). In contrast, the H4/RET type of rearrangement was related to the typical papillary type of growth. RET rearrangement-negative PTCs included slightly more follicular variants (P < 0.05). The numbers of mixed or diffuse sclerosing variants were too small to allow definite conclusions as to a specific molecular change.


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  		Table 7 Histologic variants of 191 PTCs of children as a function of the type of gene rearrangement

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Rearrangements of the RET gene are an important, if not characteristic, molecular aberration in radiation-induced thyroid carcinogenesis (21) . Thinking in terms of molecular epidemiology, it is tempting to draw a direct line from a specific carcinogenic factor—in this case, radioiodine—to a specific molecular event, e.g., a DNA double strand break and recombinational repair, to specific gene fusions (RET rearrangements) and a specific type of cancer, the PTC. Several observations support this hypothesis: The relative number of PTCs was highest in the most severely radioiodine-contaminated regions of Belarus (Gomel) in agreement with the assumption of a linear dose-response relationship (14 , 50) . Large amounts of incorporated radioiodine exert cytocidal effects in the thyroid gland with loss of thyrocytes, inflammatory reactions, and a very pronounced fibrosis, which is still present in most thyroidectomy specimen from Belarussian patients (Refs. 18 , 19 , and our own observations). Thyrocytes surviving a lethal radiation dose are targets for mutagenic effects. This target cell population is large in the thyroid glands of children because the rate of proliferation is physiologically still elevated and may be further increased by compensatory hyperplasia after radiation-induced cell loss. Proliferating cells exhibit an increased sensitivity to the mutagenic action of carcinogens (51) . Combination of an initial cell loss after high radioiodine doses and compensatory proliferation at later intervals can be envisaged as a scenario typical for the most highly contaminated areas.

It is typical to radiation that a variety of genetic lesions occurs in a randomized stochastic distribution. Only a few thyrocytes in an irradiated thyroid will undergo a biologically relevant genetic change that initiates the carcinogenic process. A critical mutation essential for tumorigenesis can only be detected in vivo if it leads to clonal expansion (52) with a selective multiplication of cells with this mutation. The majority of post-Chernobyl childhood thyroid carcinomas exhibit a RET rearrangement (21 , 39 , 46 , 53, 54, 55) . Although we have found also a few NTRK1 rearrangements in these tumors (42) , no other genetic aberration has been detected thus far that exhibits a high prevalence in these tumors similar to that found for RET rearrangements. As RET rearrangement is relatively rare in spontaneous thyroid carcinomas lacking radiation history (56) , it follows that radiation may be responsible for a DNA lesion that ends up in gene rearrangement.

The most important radiation-induced effects in this respect are DNA strand breaks (57) . The results of our previous breakpoint analysis in ELE1/RET fusions at the genomic DNA level (43) demonstrate that DNA strand breaks occur and are repaired via illegitimate recombination or DNA end joining. ELE1/RET as well as H4/RET rearrangements, the two most prevailing types of RET rearrangements, are both generated by paracentric chromosomal inversion in a small region of chromosomes 10q11.2 and 10q21 (58 , 59) , respectively. A lack of major deletions in the break-point regions (43) argues for a rapid recombination using homologous stretches of DNA as a guide (43) .

In contrast, in the novel types of RET rearrangement that we detected in a few cases (40 , 41) , RET on chromosome 10 fused with parts of genes that are located on other chromosomes.4 A balanced interchromosomal reciprocal translocation based on strand breaks on each of the two participating chromosomes might explain the rare occurrence of the novel types of RET rearrangement (PTC5-8) in post-Chernobyl tumors, most of which were found in the most highly contaminated Oblasts, Gomel and Brest. This suggests that these variants might be related to exposure to high doses of ionizing radiation.

As all RET-fused genes activate an abnormal expression of the RET TK, one would assume that the consequences of this ligand-independent RET expression are similar in all cases of PTC. However, this is not the case. The type of the RET-fused gene determines phenotype and biological as well as clinical behavior of the tumors. Compared with other tumors, PTCs with ELE1/RET rearrangements exhibit a significantly shorter latency period before tumor manifestation, are in a more advanced stage at diagnosis with an earlier extrathyroidal extension, and are significantly coupled to the histological pattern of a solid variant of PTC. ELE1/RET rearrangement thus is a radiation-induced genetic lesion characteristic of rapidly growing, aggressive PTC.

Correlations between RET rearrangements and metastatic potential have been a matter of dispute in the past. On the basis of a few cases only, we and others (39 , 60 , 61) have speculated about a possible influence of RET rearrangements on tumor stage and metastatic spread. Connections between RET/NTRK1 positivity and locally advanced stages of disease at presentation were found recently in a series of radiation-independent PTCs in Italy (36) . Although follow-up studies have not yet been possible, it might be concluded that RET or NTRK1 rearrangements are connected to a worse clinical course when compared with RET- or NTRK1-negative PTCs. The mechanisms of how RET rearrangements are involved in the increased extrathyroidal extension and metastatic spread are still obscure, but it has been shown that RET transfection endows kidney cells in vitro with an increased migration potential (62) , one of the facets of invasion.

ELE1/RET rearrangements obviously lack the morphogenetic potential to induce follicular or papillary structures. Observations in transgenic mice bearing an ELE1/RET construct support the hypothesis that it is indeed the ELE1/RET genotype that generates the histological pattern of a solid variant of PTC (63) . The histology of thyroid tumors in these mice resembled that of solid variants of PTC. PTCs with other types of rearrangement show a papillar or follicular growth pattern, as was also observed in thyroid carcinomas of H4/RET transgenic mice (64) . Thyroid carcinomas in H4/RET transgenic mice progress slowly and do not metastasize (65) , whereas in ELE1/RET transgenic mice, metastatic potential of thyroid tumors has been observed (63) .

Our results disagree with the assumption that ELE1/RET might be typical to a young age at irradiation (36 , 47) . The data show that a young age at irradiation does not favor a specific type of gene rearrangement. However, with an identical starting point, i.e., the time of the Chernobyl reactor accident, the unusually rapid mode of development of ELE1/RET tumors led, at the time of surgery, to a higher prevalence of ELE1/RET tumors in young patients. This reflects the rapid growth of PTCs harboring an ELE1/RET rearrangement rather than a young age at irradiation. The prevalence of RET rearrangements decreases and the genetic spectrum shifts toward H4/RET rearrangements with increasing time after Chernobyl, later occurring tumors more frequently contained an H4/RET rearrangement (54 , 66 , 67) . Other factors are involved in progression, e.g., female sex hormones with the large number of RET rearrangement-negative PTCs in females arising beyond puberty. The exact correlations remain to be clarified.

The dependence of phenotype and biological behavior on a specific type of gene rearrangement indicates that both parts of the fused genes contribute to the biological effects of rearrangements. The aberrant RET TK activity in thyrocytes is specifically connected to PTC. On the other side, the RET-fused gene obviously regulates the specific mode of differentiation, proliferation, and metastatic spread. The biological function of H4 is still unknown. The ELE1 gene is identical to the gene (designated ARA70) that encodes an androgen receptor transcription coactivator (34) . GOLGA5 codes for a Golgi integral membrane protein (68) , HTIF for the human transcription intermediary factor (69) , and RFG7 for a similar protein (41) . It is common to all RET-fused genes that they are ubiquitously expressed and contain dimerization domains conferring the potential for RET autophosphorylation and activation of intracellular signaling (70) . It is evident from the phenotypic differences in PTCs with specific types of rearrangement that the phenotype depends on hitherto unknown specific effects of RET-fused genes.

The molecular and phenotypic analysis of radiation-induced thyroid carcinogenesis is far from being complete. However, the finding of a close correlation between thyroid irradiation by radioiodine incorporation after the Chernobyl reactor accident and the high prevalence of RET gene rearrangements as a predominant molecular alteration and their connection to a specific morphology and biology of PTC may serve as a tool for understanding the pathogenesis of thyroid cancer. In addition, the results show that the genotype of a PTC may have an impact on the individual clinical course.


   ACKNOWLEDGMENTS
 
We acknowledge the excellent technical assistance of Andrea Eberl, Rita Koch, Dr. Sibylle Liebmann, Sigrid Madsen, and Michael Ruiter. We thank Monika Attmanspacher for photographic work and Brigitte Schult for typing the manuscript. We also thank the Otto Hug Strahleninstitut and Christine Frenzel for support of this work.


   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 Supported by grants (to H. M. R.) from the Dr. Mildred Scheel-Stiftung für Krebsforschung, Bonn, Germany, Wilhelm Sander-Stiftung, Neuburg/Donau, Germany, Matthias Lackas-Stiftung and K. L. Weigand’sche Stiftung. Back

2 To whom requests for reprints should be addressed, at Institute of Pathology, Ludwig Maximilians-University of Munich, Thalkirchner Strasse 36, D-80337 Munich, Germany. Phone: 49-89-5160-4081; Fax: 49-89-5160-4083; E-mail: hm.rabes{at}lrz.uni-muenchen.de Back

3 The abbreviations used are: PTC, papillary thyroid carcinoma; TK, tyrosine kinase; RFG, RET-fused gene. Back

4 Rabes et al. Novel types of RET rearrangements in radiation-induced papillary thyroid carcinomas: similarities and differences, manuscript in preparation. Back

Received 9/20/99; revised 12/13/99; accepted 12/14/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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