A study of the biological significance of the EML4-ALK fusion gene in radiation-associated thyroid carcinogenesis using conditional transgenic mice
Rearranged anaplastic lymphoma kinase (ALK) gene (echinoderm microtubule-associated protein-like 4 [EML4]-ALK fusion gene), which we found for the first time in papillary thyroid cancer (PTC), is likely to be highly correlated with atomic-bomb (A-bomb) radiation exposure and to occur in a fundamentally exclusive manner in RET, neurotropic tyrosine kinase receptor 1 (NTRK1), BRAF, and RAS gene alterations. Interestingly, just as lung adenocarcinoma cases with the EML4-ALK fusion gene show histological characteristics significantly different from those without the EML4-ALK fusion gene, this fusion gene-positive PTC has characteristic solid/trabecular architectures at a high frequency, suggesting that the EML4-ALK fusion gene plays a key role in architectural alterations related to the histopathological characteristics of the cancer tissue that concerns our oncology study. We thus hypothesize that the EML4-ALK fusion gene plays an important role in causing PTC and is a result of radiation. The function of the fusion gene may be different from RET/PTC rearrangements in terms of their pathological consequences. With use of conditional transgenic mice harboring the EML4-ALK gene, we will test the hypotheses from the following viewpoints: One is to evaluate evidence for generation of PTC from the transgenic mice with this fusion gene. The second is to demonstrate effects of radiation in tumorigenesis in these transgenic mice, i.e., the shortened latency and/or the enhanced aggressiveness of the tumors.