@misc{oai:repo.qst.go.jp:00062769,
 author = {Shimada, Yoshiya and Nakata, Akifumi and Imaoka, Tatsuhiko and Nishimura, Mayumi and Kakinuma, Shizuko and Yamauchi, Kazumi and Iizuka, Daisuke and Ariyoshi, Kentaro and Shang, Yi and Hatano, Yukiko and Amasaki, Yoshiko and Takabatake, Takashi and Akiyma, Miho and Yoshida, Mitsuaki and 島田 義也 and 中田 章史 and 今岡 達彦 and 西村 まゆみ and 柿沼 志津子 and 山内 一己 and 飯塚 大輔 and 有吉 健太郎 and 尚 奕 and 西村 由希子 and 甘崎 佳子 and 高畠 貴志 and 穐山 美穂 and 吉田 光明},
 month = {Mar},
 note = {Introduction
One of the major concerns about charged particles is its carcinogenic potential, which relates to cosmic ray exposure or the charged particle therapy.  It is important to estimate the risks of secondary cancer after exposure to charged particles for cancer patients. However, the available data are still insufficient.  Recently, we have commenced animal experiments in order to elucidate the effect of charged particle on cancer induction.  
\nMaterials and methods
C57BL/6 (B6) and B6C3F1 mice at 5 weeks after birth were exposed to fractionated X rays or carbon ions (SOBP) at doses 0.3 – 2.0 Gy once a week for 4 consecutive weeks to induce T-cell lymphoma.  SD rats were also irradiated at 7 weeks of age for induction of mammary carcinoma at dose of 0.2 – 4.0 Gy.  
\nResults
T-cell lymphomagenesis: The dose response of T-cell lymphoma incidence in B6 and B6C3F1 mice was bell shaped, and the RBE of carbon ions (SOBP) at 50% incidence was 1.2.  We previously demonstrated a frequent loss of heterozygosity (LOH) in the centromeric region of chromosome 11 in X-ray-induced T-cell lymphoma in B6C3F1 mice.  The LOH was rarely observed in spontaneously developed or ENU-induced lymphoma and thus it appeared to be radiation signature (Shimada et al. 2000, Kakinuma et al. 2005).  Lymphoma induced by carbon ions had much higher frequency of this LOH.  Chromosomal analysis indicated that this LOH was caused by predominantly interstitial deletion of chromosome 11 and confirmed that the aberration of chromosome 11 was much more frequent in carbon-ion-induced lymphoma than X-ray-induced one (Yoshida et al. 2007).  It was also evident that carbon-induced lymphoma exhibited an increased frequency of translocations and aneuploidy, suggesting an chromosomal instability.  
Mammary carcinogenesis;The dose response of rat mammary carcinomas was linear for gamma rays, whereas it was concave upward for carbon ions (SOBP).  RBE was around 2 at dose of 1-2Gy.  Neither p53 nor H-ras mutations were detected in any tumors (Imaoka et al. 2007).  In order to detect the molecular difference between spontaneous, gamma-ray-induced and carbon-ion-induced carcinomas, the expression profile was examined by microarrays and qPCR.  Although most of gene expressions were common, we identified 8 genes that had different expression between spontaneous and gamma-ray-induced tumors.  Analysis in carbon-induced tumors is currently undertaken if there is a difference in global and specific gene expression between gamma ray-induced and carbon ion-induced carcinomas.
\nDiscussion
Cancer therapy with carbon ions from HIMAC has been successfully conducted for these 15 years.  Since cancer prognosis has been improved much, it is needed to determine the risk of late occurring side effects of HIMAC therapy such as secondary cancer.   We here showed that RBE of carbon ions (SOBP) was not large, 1.2 for mouse T-cell lymphoma and 2 for rat mammary carcinomas.  It is reported that RBE for tumor induction in mice legs, which include histiocytoma and fibrosarcoma, is around 2 (Ando et al. 2005).  Therefore, the risk of secondary tumor induction by carbon ions might not be seriously higher than anticipated. 
We showed here frequent chromosome translocations and aneuploidy in carbon-ion induced lymphomas, suggesting an increased chromosomal instability.  This result is consistent with the previous reports that indicate complex chromosomal changes induced by heavy ions in human lymphocytes (George et al. 2003).  Together with further study on the expression profiles in carbon-ion-induced mammary tumors, the similarity and difference between the mechanism of carcinogenesis induced by X rays and that by carbon ions will be delineated., NIRS International Workshpo Particle Radiation Science},
 title = {Carcinogenesis by high LET radiation},
 year = {2008}
}