Host: The Japan Radiation Research Society, Chairman of the 52nd Annual Meeting, Toshiteru Okubo (Radiation Effects Research Foundation)
Thyroid cancer is one of the malignancies most strongly associated with ionizing radiation. Risk of papillary thyroid cancer (PTC) among atomic-bomb survivors has been found to significantly increase with radiation dose. A major early event in papillary thyroid carcinogenesis is constitutive activation of MAPK signaling pathway caused by one of the following gene alterations, which may be categorized into two types: Chromosomal rearrangements of RET and NTRK1 and gene point mutations of RAS and BRAF. Most of these alterations are known to activate not only MAPK pathway but also PI3K/AKT pathway. In fact, amplification of PIK3CA gene has been recently detected in PTC, suggesting that activation of this pathway may also be involved in papillary thyroid carcinogenesis.
To clarify relationship between radiation exposure and development of PTC, we examined gene alterations involved in MAPK signaling pathway, i.e. RET, NTRK1 and BRAF rearrangements, as well as BRAF and RAS point mutations, in 73 adult-onset PTC cases among atomic-bomb survivors. We found that relative frequency of BRAF and RAS gene point mutations in our PTC cases significantly decreased with increased radiation dose, while RET and NTRK1 chromosomal rearrangements showed a significant increase in relative frequency in the PTC cases with radiation dose. These findings indicate an important role of chromosomal rearrangements, especially RET/PTC rearrangements, in adult-onset radiation-associated PTC carcinogenesis.
Interestingly, PTC cases with no detected gene alterations were found frequently among patients who were exposed to high radiation doses and developed cancer early after exposure. This result suggests that other radiation-associated gene alterations than RET/PTC rearrangements might be involved in the development of radiation-associated PTC. In the light of this, amplification of PIK3CA gene is currently under analysis. This result will also be presented.
