@misc{oai:repo.qst.go.jp:00067918,
 author = {Iwakawa, Mayumi and Takai, Nobuhiko and Gotou, Miyako and Ando, Koichi and Imai, Takashi and 岩川 眞由美 and 高井 伸彦 and 中渡 美也子 and 安藤 興一 and 今井 高志},
 month = {Oct},
 note = {Search for genetic polymorphisms that associate with radiation-induced normal tissue injury on cancer patients
\nMayumi Iwakawa and Takashi Imai
RadGenomics Project, Frontier Research Center
National Institute of Radiological Sciences, Japan
\nIntroduction 
  Cancer patients vary considerably in normal tissue reactions after radiotherapy.  Several observations have indicated that certain genetic factors play important roles in this variability.  It has been hypothesized that the clinical radiosensitivity of normal tissues should be regarded as a so-called complex trait dependent on the cumulative effect of many minor genetic determinants.  Thus single nucleotide polymorphisms (SNPs) on certain genes may somehow associate with the severity of normal tissue reactions after radiotherapy.  It is important to uncover molecular basis underlying radiation sensitivity of normal tissues for further investigation of more complex character of cancer cells.  In this study we have aimed to search for polymorphisms that associate with normal tissue radiation sensitivity of various cancer patients to open a way for achieving individual-oriented radiotherapy with high-therapeutic ratio.
\nResearch strategy 
  Our strategy is a candidate gene approach selected through the experiments using in vitro cultured human cell lines and animal models. SNPs on the selected genes have been typed using the DNA from white blood cells of cancer patients with clinical information.
\nPatients and Methods
1.  Patients 
  The 1071 patients in this study consist 489 breast cancer patients, 149 ovarian cancer patients, 126 prostate cancer patients, 133 head and neck cancer patients.  They were registered between 2001 and 2004.  Normal tissue reactions until the 3rd month after completion of the treatment were graded according to the National Cancer Institute-Common Toxicity Criteria (NCI/CTC).  Late effects on normal tissues were graded according to the Radiation Therapy Oncology Group/ the European Organization for Research and Treatment of Cancer (RTOG/EORTC) scoring system and the Late Effects of Normal Tissues-Subjective, Objective, Management and Analytic (LENT-SOMA) scoring system.  Patients were divided into two groups (radiosensitive and radioresistant) according to the grades determined by the above scoring systems.
\n2.  Candidate gene selection 
  We have defined following three criteria to select candidate genes.  (1) Genes whose expression profile showed statistically significant association with cellular radiation sensitivity.  (2) Genes whose expression were induced or reduced after ionizing radiation treatment.  (3) Genes whose involvement in the radiation sensitivity had been evaluated in some literatures.  We have measured radiosensitivity of 32 different cultured human cancer cell lines and analyzed their gene expression profile by microarray technique.  In addition, we have analyzed in vivo gene expression profile of mouse strains with different radiation sensitivity.  As a total we have selected 108 candidate genes that met at least one of the above criteria.
\n3. SNPs typing of the candidate genes and statistical analysis
  The information about SNPs on the candidate genes was obtained from JSNP database (http://snp.ims.u-tokyo.ac.jp/) and dbSNP database (http://www. ncbi.nlm.nih.gov/SNP/). Typing of the SNPs was performed by the allele-specific termination of primer extension method using a MALDI-TOF Mass spectrometer. 
\nResults
Six hundreds and forty three SNPs were typed for the 108 candidate genes of 346 individuals consisting of 218 breast cancer patients, 57 ovarian cancer patients and 71 prostate cancer patients.  Statistical analysis of association between the SNP types and radiation sensitivity of patients has been done using SNPalyze software.  So far, we found more than 12 genes that showed statistically significant association.
\nConclusion 
  This study implies that analysis of multiple SNPs on adequately selected candidate genes might be specifically suitable for identification of genetic constraints of radiation sensitivity.  At present state our findings are still preliminary and require assignment of functional influence of the SNPs to the expression of gene activity that relate to the radiation sensitivity.  Our study should encourage further comprehensive search for genetic polymorphisms that associate with radiation-induced normal tissue injury on cancer patients
\nAcknowledgement 
  We deeply appreciate patients who accepted to participate in our study and collaborators who participated in obtaining informed consent from medical information and providing patient's blood sample. 
 
Strain-dependent differences in locomotor activity after local brain irradiation with 30 GyE of carbon ions
\nMayumi Iwakawa1, Nobuhiko Takai2, Miyako Goto1, Koichi Ando2, and Takashi Imai1
\nAbstract
\nIn this study, mice of inbred, A/J, C57BL/6J and C3H/HeMs mice were used to reveal inter-strain differences of radiosensitivity after local brain irradiation and spontaneous locomotor activity was examined as a parameter of brain function. The whole brain of the A/J, C57BL/6J and C3H/HeMs male mice was irradiated with carbon ion beams. We measured the locomotor activity determined by the Supermex system using detection of the body heat of an animal. The daily locomotor activities of non-irradiated and irradiated A/J, C57BL/6J and C3H/HeMs mice differed significantly. This inter-strain variance became obvious immediately after irradiation, as the activity of A/J mice diminished, whereas the C57BL/6J mice became hyperactive. Daily total spontaneous locomotor activity was suppressed one day after irradiation and increased thereafter among three strains. When we also measured the locomotor activity after the dopamin receptor agonist, apomorphine, treatment, a significant increase of activity in C57BL/6J mice was detected, whereas a significant decrease in C3H/HeMs or A/J mice. In conclusion, radiosensitivity of the brain determined as locomotor activity varied among three strains., ESTRO23},
 title = {Strain-dependent differences in locomotor activity after local brain irradiation with 30 GyE of carbon ions},
 year = {2004}
}