• Kiyohiro Hamatani, Hidetaka Eguchi, Reiko Ito, Mayumi Mukai, Keiko Takahashi, Masataka Taga, Kazue Imai, John Cologne, Midori Soda, Koji Arihiro, Megumu Fujihara, Kuniko Abe, Tomayoshi Hayashi, Masahiro Nakashima, Ichiro Sekine, Wataru Yasui, Yuzo Hayashi, and Kei Nakachi.
• Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima-shi, Hiroshima 732-0815, Japan. hamatani@rerf.or.jp
• Cancer Res. 2008 Sep 1; 68 (17): 7176-82.

AbstractA major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAF(V600E) point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAF(V600E) mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (P(trend) = 0.002). In contrast, BRAF(V600E) mutation was less frequent in cases exposed to higher radiation dose (P(trend) < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAF(V600E) mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis.

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