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Suitability of animal models for studying radiation-induced thyroid cancer in humans: evidence from nuclear architecture.

BACKGROUND
Rat and mouse have been widely used to estimate the radiation risk and tumorigenic effects of radiation with extrapolating the findings to humans. RET/PTC is a characteristic genetic alteration frequently found in radiation-induced thyroid cancer in human populations. Recently, nuclear architecture and spatial proximity between recombinogenic genes have been implicated as important factors in the generation of RET/PTC and other chromosomal rearrangements in human cells. However, it is unknown whether the nuclear architecture in rodent thyroid cells is similar to that of human thyroid cells. The aim of this study was to test whether the proximity effects that are observed between loci involved in RET/PTC rearrangements in humans are conserved across different species.


METHODS
Using 3D fixation, fluorescence in situ hybridization, and confocal microscopy, we compared the distance between genes involved in RET/PTC rearrangement in normal thyroid cells from humans, mice, and rats.


RESULTS
While in humans, RET, NCOA4, and H4 are all located on the same chromosome (10q), in rodents these genes are located on separate chromosomes. In mouse, RET is located on chromosome 6F1, NCOA4 on 14B, and H4 on 10B5.3. In rat, RET is on chromosome 4q42, NCOA4 on 16p16, and H4 (TST1) on 9q36. We further observed that in human thyroid cells, mean distance between genes involved in two most common types of RET/PTC, that is, RET and NCOA4 (partners of RET/PTC3) and RET and H4 (partners of RET/PTC1), was 1.08±0.04 and 1.24±0.05 μm, respectively. In mouse thyroid cells, these distances were 3.21±0.1 and 3.43±0.1 μm, and in rat cells the values were 3.37±0.1 and 3.87±0.1 μm (p<0.001). Moreover, we found that in contrast to human thyroid cells, in rodent cells these genes were randomly positioned with respect to each other.


CONCLUSIONS
The differences in nuclear architecture and spatial positioning of genes involved in RET/PTC rearrangements between human and rodent thyroid cells raise a concern about suitability of animal models for assessing RET/PTC-driven thyroid carcinogenesis in humans.