Challenging Dogma in Thyroid Cancer Molecular Genetics—Role of RET/PTC and BRAF in Tumor Initiation

JA Fagin - The Journal of Clinical Endocrinology & Metabolism, 2004 - academic.oup.com
The Journal of Clinical Endocrinology & Metabolism, 2004academic.oup.com
RET/PTC oncogenes are believed to play an important role in the pathogenesis of a
significant subset of papillary carcinomas of the thyroid (PTC), in particular those arising
after radiation exposure, and in pediatric cancers. Chromosomal rearrangements linking the
promoter and N-terminal domains of unrelated gene/s to the C-terminal fragment of RET
result in the illegitimate expression of a chimeric form of the receptor in thyroid cells that is
constitutively active (1). Several molecular forms have been identified that differ according to …
RET/PTC oncogenes are believed to play an important role in the pathogenesis of a significant subset of papillary carcinomas of the thyroid (PTC), in particular those arising after radiation exposure, and in pediatric cancers. Chromosomal rearrangements linking the promoter and N-terminal domains of unrelated gene/s to the C-terminal fragment of RET result in the illegitimate expression of a chimeric form of the receptor in thyroid cells that is constitutively active (1). Several molecular forms have been identified that differ according to the 5 partner gene involved in the rearrangement, with RET/PTC1 and RET/PTC3 being the most common. RET/PTC1 is formed by a paracentric inversion of the long arm of chromosome 10 leading to fusion of RET with a gene named H4/D10S170. RET/PTC3 is also a result of an intrachromosomal rearrangement and is formed by fusion with the RFG/ELE1 gene. RET/PTC is believed to be one of the key first steps in thyroid cancer pathogenesis because: 1) There is a high prevalence of RET/PTC expression in occult or microscopic PTC (2–4), pointing to the activation of this oncogene at early stages of tumor development. 2) Thyroidspecific overexpression of either RET/PTC1 (5, 6) or RET/PTC3 (7) in transgenic mice leads to development of tumors with histological features consistent with papillary thyroid carcinoma, indicating that these oncoproteins can recreate the disease in an animal model. 3) Exposure of cell lines (8) and fetal thyroid explants (9) to ionizing radiation results in expression of RET/PTC within hours, supporting a direct role for radiation in the illegitimate recombination of RET. 4) The breakpoints in the RET and ELE1/RFG genes resulting in the RET/PTC3 rearrangements of radiation-induced pediatric thyroid cancers from Chernobyl are consistent with direct double-strand DNA breakage resulting in illegitimate reciprocal recombination (10). Moreover, the H4 and RET genes, although lying at a considerable linear distance from each other within chromosome 10, are spatially juxtaposed during interphase in thyroid cells and presumably present a target for simultaneous double-strand breaks in each gene after ionizing radiation, thus giving rise to the RET/PTC1 rearrangement (11). These data provide evidence that ionizing radiation, the major risk factor for development of papillary thyroid cancer, can directly induce RET recombination events and link environmental agents to tumor initiation through this genetic pathway. The paper by Unger et al.(12) in this issue of the JCEM potentially adds a new dimension to our understanding of the role of RET/PTC in thyroid cancer pathogenesis. The authors used fluorescence in situ hybridization with differentially labeled fluorescent yeast artificial chromosome probes complementary to the region of the RET gene immediately upstream of the recombination (labeled in green) or downstream (labeled in red) to detect rearrangements in interphase cells of papillary cancer specimens. A rearranged RET gene would manifest as a split of the red and green signals. Using this approach, they confirmed a high prevalence of RET/PTC rearrangements in papillary thyroid cancers from Ukrainian patients exposed to radiation after the Chernobyl nuclear accident. However, there was considerable heterogeneity within the tumor specimens, in which only a small proportion of cells harbored the rearrangement. The regions with or without RET rearrangements tended to cluster in different regions of the tumor. The authors took care to microdissect the tissue samples to minimize the number of nontumoral cells in the specimen. They used confocal microscopy to examine the full …
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