Abstract
Ionizing radiation produces various types of DNA damage, which have a potential to lead to specific gene mutations that initiate carcinogenesis. Chromosomal rearrangements are common after radiation exposure and most likely result from mis-rejoining of two radiogenic double-strand DNA breaks. Recent studies have shown that chromosomal rearrangements, such as those involving the RET and BRAF genes, are a dominant mechanism of carcinogenesis in radiation-induced thyroid cancer in humans, whereas point mutations of BRAF and RAS more frequently activate the same MAPK signaling pathway in sporadic tumors. RET/PTC rearrangements result from a paracentric inversion of chromosome 10q and are highly prevalent in radiation-associated thyroid tumors in human populations and can be induced by cell irradiation in vitro. Over the last decade, it has become evident that spatial proximity between potential recombinogenic partners is an important prerequisite for the generation of chromosomal exchanges. Interphase proximity of RET/PTC partners has been identified in normal human thyroid cells. This non-random positioning is most likely due to the large-scale chromosome folding in this region, which brings the recombinogenic-prone genes closer to each other in the interface nuclei of normal cells. Spatial proximity may facilitate the rearrangement by placing two free DNA ends close in space and time within the nuclear volume.
