ヒト集団の長期追跡に基づく発がんと免疫の分子疫学研究

• Project/Area Number: 17015053
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Radiation Effects Research Foundation
• Principal Investigator: 中地 敬 (財)放射線影響研究所, 放射線生物学/分子疫学部, 部長(研究員) (00142117)
• Co-Investigator(Kenkyū-buntansha): 楠 洋一郎 (財)放射線影響研究所, 放射線生物学/分子疫学部, 副部長(研究員) (60333548) ; 林 奉権 (財)放射線影響研究所, 放射線生物学/分子疫学部, 室長(研究員) (70333549)
• Project Period (FY): 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥8,300,000 (Direct Cost: ¥8,300,000); Fiscal Year 2005: ¥8,300,000 (Direct Cost: ¥8,300,000)
• Keywords: 免疫 / ハプロタイプ解析 / NKG2D / 炎症 / 原爆放射線 / IL-10 / GPA

Research Abstract

埼玉コーホート研究と原爆被爆者免疫コーホート研究を統合して、免疫、炎症、放射線被曝、発がんの関係を明らかにするのが本研究の目標である。埼玉コーホート研究により、末梢血リンパ球のNK活性の主たる遺伝的要因が活性型受容体NKG2D遺伝子領域のハプロタイプであることを見出し、コーホート内症例対照研究によりNKG2Dハプロタイプの発がんリスクを評価した。NK活性が低いハプロタイプを持つ人は一般集団の32%を占め、かつ発がんリスクも約2倍高いことになり、発がん全体への大きな寄与危険を示した。さらに、環境因子がNK活性に与える影響の程度は個人個人のNKG2Dハプロタイプによって異なることが示唆された。免疫学的がん予防はがん以外の免疫・炎症関連疾患の予防とも重複した効果を期待でき、今後の重要な研究課題と考える。現在、原爆被爆者免疫コーホートにおいてNKG2Dハプロタイプの発がんリスクと放射線被曝の関係を検討すべく準備している。原爆被爆者免疫研究では、放射線被曝と炎症性免疫の関係を示した。すなわち、一連の炎症指標で示される亜臨床的炎症状態は加齢によって亢進するが、被爆者では被曝線量に応じて炎症状態がさらに亢進する。1Gyの放射線被曝は、9年の加齢による炎症状態の亢進に相当する影響を与える。また、ゲノム解析により、炎症の指標の一つであり免疫抑制作用を持つIL-10遺伝子領域に同定したハプロタイプが、放射線被曝とともに原爆被爆者の胃がん発生に強く関連していることを見出した。このハプロタイプは血漿IL-10濃度と強く関連した。さらに、原爆被爆者免疫コーホートの10年の追跡調査により、変異性の指標である赤血球GPA変異率の被曝線量による増加の割合ががん罹患群では非罹患群に比べ顕著に大きいことを見出した。NK活性の場合と同様の表現型・遺伝子型関連解析より、放射線感受性の遺伝要因を探索中である。

Research Products

• [Journal Article] Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral-blood lymphocytes and cancer immunosurveillance. (2006)
  • Author(s): Hayashi, T., Imai, K., Morishita, Y., Hayashi, I., Kusunoki, Y., Nakachi, K.
  • Journal Title: Cancer Res. 66 Pages: 563-570
• [Journal Article] Suberoylanilide hydroxamic acid enhances gap junctional intercellular communication via acetylation of histone containing connexin 43 gene locus. (2005)
  • Author(s): Ogawa, T., Hayashi, T., Tokunou, M., Nakachi, K., Trosko, J.E., Chang, C-C., Yorioka, N.
  • Journal Title: Cancer Res. 65 Pages: 9771-9778
• [Journal Article] Individual variation of somatic gene mutabiity in relation to cancer susceptibility : Prospective study on erythrocyte glycophorin A gene mutations of atomic bomb survivors. (2005)
  • Author(s): Kyoizumi, S., Kusunoki, Y., Hayashi, T., Hakoda, M., Cologne, J.B., Nakachi, K.
  • Journal Title: Cancer Res. 65 Pages: 5462-5469
• [Journal Article] Cytogenetic differences in breast cancer samples between German and Japanese patients. (2005)
  • Author(s): Packeisen, J., Nakachi, K., Boecker, W., Brandt, B., Buerger, H
  • Journal Title: J.Clin.Pathol. 58 Pages: 1101-1103
• [Journal Article] Clinicopathological significant and prognostic influence of cadherin-17 expression in gastric cancer. (2005)
  • Author(s): Ito, R., Oue, N., Yoshida K., Kunimitsu, K., Nakayama, H., Nakachi, K., Yasui, W
  • Journal Title: Virchows Archiv. 447 Pages: 717-722
• [Journal Article] A single nucleotide polymorphism in the extracellular domain of TRAIL receptor DR4 at nucleotide 626 in gastric cancer patients in Japan. (2005)
  • Author(s): Kuraoka, K., Matsumura S., Sanada, V., Nakachi, K., Imai, K., Eguchi, H., Matsusaki, K., Oue, N., Nakayama.H., Yasui, W
  • Journal Title: Oncol.Rep. 14 Pages: 465-470
• [Journal Article] Stabitity of frozen serum levels of insulin-like growth factor-I, insulin-like growth factor-II, insulin-like growth factor binding protein-3 transforming growth factor beta, soluble Fas, and superoxide dismutase activity for the JACC study. (2005)
  • Author(s): Ito, Y., Nakachi, K., Imai, K., Hashimoto, S., Watanabe, Y., Inaba, Y., Tamakoshi, A., Yoshimura, T.: JACC Study Group
  • Journal Title: J.Epidemiol. 15(Suppl.1)
• [Journal Article] Smoking and elevated blood pressure are the most important risk factors for subarachnoid hemorrhage in the Asia-Pacific region : An overview of 26 cohorts involving 306,620 participants. (2005)
  • Author(s): Members of Asia Pacific Cohort Studies Collaboration, Nakachi, K.
  • Journal Title: Stroke 36 Pages: 1360-1365
• [Journal Article] A comparison of the associations between risk factors an cardiovascular disease in Asia and Australasia. (2005)
  • Author(s): Members of Asia Pacific Cohort Studies Collaboration, Nakachi, K
  • Journal Title: J.Cardiovascular Prev.Rehab. 12 Pages: 484-491
• [Journal Article] A comparison of lipid variables as predictors of cardiovascular disease in the Asia-Pacific region. (2005)
  • Author(s): Members of Asia Pacific Cohort Studies Collaboration, Nakachi, K.
  • Journal Title: Annals of Epidemiology 15 Pages: 405-413
• [Journal Article] Does sex matter in the associations between classic risk factors and fatal coronary hear disease in populations from the Asia-Pacific region? (2005)
  • Author(s): Members of Asia Pacific Cohort Studies Collaboration, Nakachi, K
  • Journal Title: J.Women's Health (Larchmt) 14 Pages: 820-828
• [Journal Article] Joint effects of systolic blood pressure and serum cholesterol on cardiovascular disease in the Asia-Pacific region. (2005)
  • Author(s): Members of Asia Pacific Cohort Studies Collaboration, Nakachi. K
  • Journal Title: Circulation 112 Pages: 3384-3390
• [Journal Article] A single nucleotide polymorphism in the 5' untranslated region of the EGF gene is associated with occurrence and malignant progression of gastric cancer. (2005)
  • Author(s): Hamai, Y., Matsumura, S., Matsusaki, K., Kitadai, Y., Yoshida, K., Yamaguchi, Y., Imai, K., Nakachi, K., Toge, T., Yasui, W.
  • Journal Title: Pathobiology 72 Pages: 133-138
• [Journal Article] Detection of plasma hnRNP B1 mRNA, a new cancer biomarker, in lung cancer patients by quantitative real-time Polymerase Chain Reaction. (2005)
  • Author(s): Sueoka, E., sueoka, N., Iwanaga, K., Sato, A., Suga, K., Hayashi, S-I., Nagasawa, K., Nakachi, K.
  • Journal Title: Lung Cancer 48 Pages: 77-83
• [Journal Article] Single nucleotide polymorphisms in the EXO1 gene and risk of colorectal cancer in a Japanese population. (2005)
  • Author(s): Yamamoto, H., Hanafusa, H., Ouchida, M., Yano, M., Suzuki, H., Murakaimi, M., Aoe, M., Shimizu, N., Nakachi, K., Shimizu, K.
  • Journal Title: Carcinogenesis 26 Pages: 411-416
• [Journal Article] Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients. (2005)
  • Author(s): Yuasa, Y., Nagasaki, H., Akiyama, Y., Sakai, H., Nakajima, T., Ohkura, Y., Takizawa, T., Koike, M., Tani, M., Iwai, T., Sugihara, K., Imai, K.m Nakachi, K.
  • Journal Title: Carcinogenesis 26 Pages: 193-200
• [Journal Article] Long-term effects of radiation dose on inflammatory markers in atomic bomb survivors. (2005)
  • Author(s): Hayashi, T., Morishita, Y., Kubo, Y., Kusunoki, Y., Hayashi, I., Kasagi, F., Hakoda, M., Kyoizumi, S., Nakachi.K
  • Journal Title: Am.J.Med. 118 Pages: 83-86
• [Journal Article] A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer. (2005)
  • Author(s): Matsumura, S., Oue, N., Nakayama, H., Kitadai, Y., Yoshida, K., Yamaguchi, Y., Imai, K., Nakachi, K., Chayama, K., Yasui, W.
  • Journal Title: J.Cancer Res.Clin.Oncol. 131 Pages: 19-25
• [Journal Article] Improved RT-PCR amplification for molecular analyses with long-term preserved formalin-fixed, paraffin-embedded tissue specimens.
  • Author(s): Hamatani, K., Eguchi, H., Takahashi, K., Koyama, K., Mukai, M., Ito, R., Taga, M., Yasui, W., Nakachi.K.
  • Journal Title: J.Histochem.Cytochem. in press
• [Journal Article] Single nucleotide polymorphism at codon 133 of the RASSF1 gene is preferentially associated with human lung adenocarcinoma risk.
  • Author(s): Kanzaki, H., Hanafusa, H., Yamamoto, H., Yasuda, Y., Imai, K., Yano, M., Aoe, M., Shumizu, N., Nakachi, K., Ouchida, M., Shimizu, K.
  • Journal Title: Cancer Lett. in press