Preventive Medicine / Individualized Medicine by Use of Epigenotyping

• Project/Area Number: 17390162
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: MAEKAWA Masato Hamamatsu University School of Medicine, 医学部, MD, Professor (20190291)
• Co-Investigator(Kenkyū-buntansha): TAKESHITA Akihiro Hamamatsu University School of Medicine, 医学部, Associate Professor (00242769) ; IINO Kazumi Hamamatsu University School of Medicine, Hospital, Assistant Professor (90402263) ; WATANABE Yoshihisa Hamamatsu University School of Medicine, 医学部, Assistant Professor (00362187) ; 堀井 俊伸 浜松医科大学, 医学部附属病院, 助手 (80283430) ; 白井 直人 浜松医科大学, 医学部, 助手 (90362194)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥900,000); Fiscal Year 2007: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2006: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2005: ¥8,400,000 (Direct Cost: ¥8,400,000)
• Keywords: DNA methylation / Epimutation / Urinary tract cancer / BNIP3 / SARP2 / Methylation analysis / メチル化解祈 / 大腸癌 / hMLH1 / hMSH2 / p16 / 血液悪性腫瘍 / 固形癌 / 遺伝子発現 / 低メチル化 / SNCG / JAK2 / RUNX1

Research Abstract

We designed comparative studies of epigenotype and phenotype relationship by using pathological tissues as well as peripheral blood cells, especially in cancer.
Synuclein γ (SNCG) gene expression was down-regulated by DNA methylation and up-regulated by DNA hypomethylation by methylation analysis using cancer cell lines. In leukemia, gastrointestinal cancer and brain tumor, hypomethylation and up-regulation of SNCG was observed. In DNA prepered from peripheral blood of healthy individuals SNCG was methylated and not expressed
Colorectal cancer specimens were analyzed for microsatellite instability and DNA methylation of mismatch repair genes, h MSH2 and hMLH1. No epimutation was discovered
Urinary tract cancer specimens were subjected for DNA methylation and mRNA expression analysis of LDHA LDHB, CKB, CKM, SNCG, MAD2, NPTX2, SARP2, p16, GSTP1 and BNIP3. SARP2 was strongly expressed in normal adjacent tissues but weakly expressed in cancer tissues. Twelve out of 14 cancer tissues and 7 of normal tissues SARP2 was methylated, however, epimutation was not observed in blood leukocytes and urinary sediments. Six out of 14 cancer tissues showed BNIP3 hypemethylation and down-regulation of gene expression Two normal tissues also showed BNIP3 methylation, however, its methylation degree was lower in normal tissues than in cancer tissues.
Epigenotypes regulate tissue-specifically and time-specifically gene expression. However, the regulation mechanism is not uniform but different among cases.

Research Products

• [Journal Article] Epigenetics Relations to Disease and Laboratory Findings. (2007)
  • Author(s): Maekawa M, Watanabe Y
  • Journal Title: Curr Med Chem 14 Pages: 2642-2653
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] P53-dependent change in replication timing of the human genome. (2007)
  • Author(s): Watanabe Y, Shibata K, Sugimura H, Maekawa M.
  • Journal Title: Biochem Biophys Res Comm 364 Pages: 289-293
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 新規腫瘍マーカーによる膵癌早期診断の可能性 (2007)
  • Author(s): 前川真人
  • Journal Title: 医学のあゆみ 222(1) Pages: 45-50
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] LOCI法 (2007)
  • Author(s): 前川真人
  • Journal Title: Medical Technology 35(9) Pages: 894-894
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 遺伝子診断の実際 酵素異常症(LDサブユニット欠損症、コリンエステラーゼ変異) (2007)
  • Author(s): 前川真人
  • Journal Title: 臨床検査 51(12) Pages: 1444-1448
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 高LD血症の原因検索、特にLDアイソザイム解析から見出された知見 (2007)
  • Author(s): 石川仁子、前川真人
  • Journal Title: 生物物理化学 51 Pages: 243-246
  • NAID: 10020020310
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Epigenetics Relations to Disease and Laboratory Findings (2007)
  • Author(s): Maekawa, M., Watanabe, Y
  • Journal Title: Curr Med Chem 14 Pages: 2642-2653
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] p53-dependent change in replication timing of the human genome (2007)
  • Author(s): Watanabe, Y., Shibata K., Sugimura, H., Maekawa, M
  • Journal Title: Biochem Biophys Res Comm 364 Pages: 289-293
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] p53-dependent change in replication timing of the human genome. (2007)
  • Author(s): Watanabe Y.Shibata K, Suginmra H Maekawa M,
  • Journal Title: Biochem Biophys Res Cornm 364 Pages: 289-293
  • Peer Reviewed
• [Journal Article] 新規腫瘍マーカーによる膵癌早期診断の可能性 (2007)
  • Author(s): 前川 真人
  • Journal Title: 医学のあゆみ 222(1) Pages: 45-50
  • Peer Reviewed
• [Journal Article] LOCI法 (2007)
  • Author(s): 前川 真人
  • Journal Title: Medical Technology 35(9) Pages: 894-894
  • Peer Reviewed
• [Journal Article] 遣伝子診断の実際酵素異常症(LDサブユニット欠損症、コリンエステラーゼ変異) (2007)
  • Author(s): 前川 真人
  • Journal Title: 臨床検査 51(12) Pages: 1444-1448
  • Peer Reviewed
• [Journal Article] 高LD血症の原因検索、特にLDアイソザイム解析から見出された知見 (2007)
  • Author(s): 石川 仁子、前川 真人
  • Journal Title: 生物物理化学 51 Pages: 243-246
  • NAID: 10020020310
  • Peer Reviewed
• [Journal Article] 新規イムノアッセイ法。 (2007)
  • Author(s): 前川真人
  • Journal Title: 医学のあゆみ 220(10) Pages: 853-854
• [Journal Article] 遺伝子メチル化の臨床検査に及ぼす影響に関する研究 Effects of DNA Methylation on Clinical Laboratory Data. (2007)
  • Author(s): 石川仁子, 谷口照美, 浦本 武, 竹下明裕, 前川真人
  • Journal Title: 日本臨床検査自動化学会会誌別刷 32(1) Pages: 12-18
• [Journal Article] Dilution Test for Differentiating Falsely High Serum Free Triiodothyronine Concentrations. (2006)
  • Author(s): Iwahara K, Tanabe C, Maekawa M
  • Journal Title: Clin Chem 52(9) Pages: 1828-1829
• [Journal Article] Serum Tumor Makers for Pancreatic Cancer : The Dawn of New Era? (2006)
  • Author(s): Okusaka T, Yamada T, Maekawa M
  • Journal Title: J Pancreas 7(4) Pages: 332-336
• [Journal Article] An Immunoglobulin Al that Inhibits Lactate Dehydrogenase Activity, with Reversal of Inhibition by Addition of NADH. (2006)
  • Author(s): Fujita K, Sato H, Kameko F, Terasawa F, Okumura N, Sugano M, Yamauchi K, Maekawa M, Sakurabayashi I
  • Journal Title: Ann Clin Lab Sci 36(4) Pages: 461-468
• [Journal Article] Pilot study of arbitrarily primed PCR-single stranded DNA conformation polymorphism analysis for screening genetic polymorphisms related to specific phenotypes. (2005)
  • Author(s): Maekawa M, Taniguchi T, Uramoto T, Higashi H, Horii T, Takeshita A, Sugimura H, Kanamori M.
  • Journal Title: Clin Chim Acta 355 Pages: 181-184
• [Journal Article] Increased creatine kinase BB activity and CKB mRNA expression in patients with hematologic disorders : relation to methylation status of the CKB promoter. (2005)
  • Author(s): Ishikawa J, Taniguchi T, Takeshita A, Maekawa M.
  • Journal Title: Clin Chim Acta 361 Pages: 135-140
• [Journal Article] Increased serum alkaline phosphatase activity originating from neutrophilic leukocytes. (2005)
  • Author(s): Izumi M, Ishikawa J, Takeshita A, Maekawa M.
  • Journal Title: Clin Chem 51 Pages: 1751-1752
• [Journal Article] Delayed recovery of normal hematopoiesis in arsenic trioxide treatment of acute promyelocytic leukemia : a comparison to all-trans retinoic acid treatment. (2005)
  • Author(s): Shinjo K, Takeshita A, Sahara N, Kobayashi M, Nakumura S, Shigeno K, Naito K, Maekawa M, Ohnishi K, Ohno R.
  • Journal Title: Intern Med 44 Pages: 818-824
  • NAID: 130000076342
• [Journal Article] Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells. (2005)
  • Author(s): Takeshita A, Shinjo K, Naito K, Matsui H, Sahara N, Shigeno K, Horii T, Shirai N, Maekawa M, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Leukemia 19 Pages: 1306-1311
• [Journal Article] エピジュネティクスが臨床検査とどのように関わるか
  • Author(s): 前川真人
  • Journal Title: 日本臨床検査自動化学会会誌 (印刷中)
• [Presentation] An educational case showing unexpected low glycated hemoglobin value, macrocytic anemia and thrombocythemia (2007)
  • Author(s): Hamada H, Maekawa M
  • Organizer: American Association for Clinical Chemistry
  • Place of Presentation: SanDiego, USA
  • Year and Date: 2007-07-18
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] American Association for ClinicalChemistry (2007)
  • Author(s): Hamada, H., Maekawa, M
  • Organizer: An educational case showing unexpected low glycated hemoglobin value, macrocytic anemia and thrombocythemia
  • Place of Presentation: SanDiego USA
  • Year and Date: 2007-07-18
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] An educational case showing une.pected low glycated hemoglobin value, macrocytic canemia and thrombocythemia (2007)
  • Author(s): Hamada H.Maekawa M
  • Organizer: American Association for Clinical Chemistry
  • Place of Presentation: SanDiego, USA
  • Year and Date: 2007-07-18
• [Presentation] Lactate dehydrogenase M(A)subunit deficiency, the 9th homozygous patient in Japan, a case report (2007)
  • Author(s): Maekawa M, Taniguchi T, Watanabe H, Takeshita A, Aoshima M, Takigawa M, Kanno T,
  • Organizer: American Association for Clinical Chemistry
  • Place of Presentation: SanDiego, USA
  • Year and Date: 2007-07-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Lactate dehydrogenase M(A)subunit deficiency, the 9th homozygous patient in Japan, a case report (2007)
  • Author(s): Maekawa, M., Taniguchi T., Watanabe, H., Takeshita, A., Aoshima, M., Takigawa, M., Kanno, T
  • Organizer: American Association for Clinical Chemistry
  • Place of Presentation: SanDiego USA
  • Year and Date: 2007-07-17
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Lactated ehydrogenase M(A)subunit deficiency, the 9th homozygous patient in Japan, a case report (2007)
  • Author(s): Maekawa M, Taniguchi T, Watanabe H, Takeshita A, Aoshima M, Takigawa M, Kano T.
  • Organizer: American Association for Clinical Chemistry
  • Place of Presentation: SanDiego, USA
  • Year and Date: 2007-07-17