La tumorigenèse épithéliale thyroïdienne associée aux radiations.

Abstract

Les tumeurs thyroïdiennes associées aux radiations ont été observées chez les survivants d’explosions atomiques, dans les populations contaminées lors d’essais ou d’accidents nucléaires et chez des patients traités par irradiation. A ce jour, l’irradiation est le seul agent étiologique définitivement reconnu de la cancérogenèse thyroïdienne chez l’homme. L’état actuel des recherches a établi la participation de six gènes dans le processus de tumorigenèse épithéliale thyroïdienne « spontanée » : RAS, GSP, RET, TRK, P53 et TSH-R ainsi que le rôle clé des réarrangements du proto-oncogène ret, de type RET/PTC 1 ou RET/PTC3. De plus, les gènes lésés, RAS, GSP ou RET, pourraient collaborer avec un (ou plusieurs) autre(s) gène(s) pour déclencher une croissance anarchique du thyrocyte. Une meilleure connaissance du mécanisme de transformation cellulaire induite par les radiations ionisantes et des altérations génétiques responsables de son déclenchement devrait permettre une amélioration du traitement mais aussi probablement une prévention plus efficace.

Studies from different laboratories have firmly established the involvement of 6 genes in the @?spontaneous@? epithelial thyroid tumorigenic process: ras, gsp, ret, trk, p53 and TSH-R. The major hazar from ionizing radiation in man, is the induction of follicular cell thyroid tumors, but not all the patients develop a tumor after external therapeutic radiation for benign or malignant conditions, or after a nuclear accident. The age at the moment of irradiation is a major factor of radiosensibility. The results concerning the study of the ras and gsp genes showed : (1) that the overall frequency of ras and gsp activating mutations, was not significantly different in @?spontaneous@? and radiation-associated thyroid tumors; (2) that all three ras genes are mutated in radiation associated tumors with similar frequencies, as described for @?spontaneous@? tumors, and (3) a difference in the mechanism of mutation of ras and gsp in @?spontaneous@? and radiation-associated tumors. Indeed, whereas in @?spontaneous@? tumors, transversions as well as transitions were detected, in radiation-associated tumors, only transversions were present. Five oncogenically activated forms of the ret proto-oncogene designated RET/PTC1, PTC2, PTC3, PTC4 and PTC5 have been identified in radiation-associated epithelial thyroid tumors. Two type of radiation-associated thyroid tumors were studied for ret : tumors originated in children contaminated by the Chernobyl fallout, and tumors obtained from patients who had received external radiation for benign or malignant conditions. The results of these studies showed that the ret proto-oncogene activating rearrangements resulting from a therapeutic or accidental ionizing radiation, plays a crucial role in the development of the thyroid radio-induced tumorigenic process. They also suggested that the ret chimeric genes predominantly originated by therapeutic or accidental ionizing radiation, are different (PTC1 and PTC3 respectively). However, in both cases they arise from an intrachromosomal rearrangement and the data indicated that ret is a common target for radiation, participating in the pathogenesis of both radiation-associated follicular adenomas and papillary carcinomas, through the formation of similar RET/PTC rearrangements. The simultaneous activation of 2 genes in the same radiation-induced thyroid tumor is a rare event, suggesting an alternative role for ras, gsp, and ret in the initiation and/or progression of the tumorigenic process. [References: 46]