title: RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose.
abstract: A 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.
authors.affiliation: Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima-shi, Hiroshima 732-0815, Japan. hamatani@rerf.or.jp
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Hamatani
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Eguchi
authors.forename: Reiko
authors.initials: R
authors.lastname: Ito
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mukai
authors.forename: Keiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masataka
authors.initials: M
authors.lastname: Taga
authors.forename: Kazue
authors.initials: K
authors.lastname: Imai
authors.forename: John
authors.initials: J
authors.lastname: Cologne
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.forename: Megumu
authors.initials: M
authors.lastname: Fujihara
authors.forename: Kuniko
authors.initials: K
authors.lastname: Abe
authors.forename: Tomayoshi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakashima
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sekine
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Kei
authors.initials: K
authors.lastname: Nakachi