Endocrine Abstracts

Recent studies support a causal relationship between radiation, formation of RET/PTC rearrangements, and development of papillary carcinomas. The evidence that RET/PTC rearrangements result directly from radiation-induced DNA damage is compelling, and further substantiated by evidence that predisposition to radiation-induced intrachromosomal inversions involving the RET gene may be favored by the three-dimensional organization of human chromosome 10 during interphase. Thus, illegitimate activation of RET is a common initiating hit in papillary thyroid cancer formation. However, expression of RET/PTC results in a relatively weak oncogenic drive. RET expression is common in micropapillary carcinomas, which rarely progress to clinically overt disease. Moreover, acute RET/PTC expression in well-differentiated thyroid cells is accompanied by stimulation of DNA synthesis as well as of apoptosis, resulting in no net growth of the cell population. RET/PTC activation is not associated with large-scale genomic destabilization in vitro, which may explain the relative rarity of aneuploidy in papillary thyroid cancers.

By contrast, radiation is not a significant risk factor for development of follicular carcinomas (FC), and RET/PTC rearrangements are not involved. FC are thought to arise from follicular adenomas, although concrete proof of this phenotypic progression is lacking. Activating mutations of RAS have been implicated in initiation of this tumorigenesis pathway. Acute expression of oncogenic RAS in well-differentiated rat thyroid follicular cells results in marked genomic destabilization within the first few cell cycles after activation. This manifests as high rates of chromosome misalignment, centrosome amplification, formation of mitotic bridges and whole chromosome losses. These effects are transduced through MAP kinase, and result in accelerated progression through the G2-M phases of the cell cycle and loss of integrity of the DNA damage and mitotic checkpoints. Ultimately, most RAS-activated cells will die through apoptosis. We propose that those that survive may initiate a tumor clone, with a predisposition to aneuploidy, resulting in formation of follicular adenomas, and more rarely, follicular carcinomas.