High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation

Abstract

A high frequency (about 60%) of ret rearrangements in papillary thyroid carcinomas of children exposed to radioactive fallout in Belarus after the Chernobyl accident, has been reported by three recent studies Ito et al., 1994;Klugbauer et al., 1995). These studies suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In order to con®rm the postulated link between irradiation and the role of the ret protooncogene in thyroid tumorigenesis, we analysed for the presence of ret activating rearrangements using RT ± PCR, XL ± PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors (19 papillary carcinomas and 20 follicular adenomas), from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 spontaneous' tumors (20 papillary carcinomas and 19 follicular adenomas). Our data concerning the radiationassociated tumors, showed that: (1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; (2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1 instead of the RET/PTC3 and (3) all the tumors were negative for RET/PTC2. In the`spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15% : 3/20): 1 RET/PTC1, 1 RET/ PTC3 and 1 uncharacterized. In conclusion, our results con®rm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors appearing after therapeutic or accidental ionizing irradiation, and show, for the ®rst time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.

Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence

“…Rearrangements of the ret protooncogene (RET/PTC) appear to occur with greater frequency in thyroid carcinomas that develop after ionizing radiation and after both low-dose and high-dose external beam radiation compared with thyroid malignancies that develop in nonirradiated individuals. [25][26][27] Although there is some disagreement among investigators, 28 it has been hypothesized that RET/PTC rearrangements are among the very first genetic changes responsible for the development of radiation-associated papillary carcinoma. 29 Nonetheless, these molecular genetic aberrations have not been correlated with the clinical characteristics or behavior of these tumors.…”

“…29 Nonetheless, these molecular genetic aberrations have not been correlated with the clinical characteristics or behavior of these tumors. [25][26][27][28] It is important to note that our series was confined to thyroid lesions that were clinically apparent (i.e., lesions that were discovered during routine physical examination). For populations that are screened using more sensitive modalities, such as thyroid ultrasound, the absolute number of abnormalities detected as well as the frequency of multinodularity likely will be increased.…”

Papillary thyroid carcinoma: 6 cases from 2 families with associated lymphocytic thyroiditis harbouring RET/PTC rearrangements

“…Indeed, contrasting with the high and very similar frequency (about 60%) of activation by rearrangement observed in the therapeutic or accidental radiation-associated tumours (Bounacer et al, 1997), the frequency of ret activation by this mechanism in 'spontaneous' thyroid tumours varies widely between different studies: from 2.5% to 34% (Bongarzone et al, 1989(Bongarzone et al, , 1993Grieco et al, 1990;Santoro et al, 1994;Delvincourt et al, 1996;Bounacer et al, 1997). It has been postulated that this variation observed in 'spontaneous' tumours, could be the result of the different geographical origins of populations studied, the age at tumour occurrence, or the sensitivity of the experimental methods used to detect the rearrangement.…”

“…All the RET/PTC oncogenic forms of ret, seem to be specific of PTCs. However, the chimeric transcript of RET/PTC1 oncogene, has also been found in one study, in radiation-associated follicular adenomas (Bounacer et al, 1997).…”

“…The activated ret oncogene was first isolated by the transfection of NIH-3T3 cells with DNA from a human T cell lymphoma (Takahashi et al, 1988). Germline point mutations of ret have been described in patients afflicted by MEN 2A and MEN 2B syndromes or familial medullary thyroid carcinoma (FMTC), indicating an involvement of ret in the pathogenesis of these diseases (Chappuis et al, 1996;Bounacer et al, 1997). In 'spontaneous' or radiation-associated PTCs, 8 forms of the ret proto-oncogene activated by rearrangement have been identified and designated RET/PTC1 to RET/PTC8 (Jhiang, 2000;Klugbauer et al, 2000).…”