小児期の放射線、化学療法によるゲノム障害の二次癌発症および遺伝的伝播に関する検討

2015 Fiscal Year Annual Research Report

• Project/Area Number: 15K15644
• Research Institution: Hiroshima University
• Principal Investigator: 檜山 英三 広島大学, 自然科学研究支援開発センター, 教授 (00218744)
• Co-Investigator(Kenkyū-buntansha): 栗原 將 広島大学, 大学病院, 医科診療医 (40724894)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Keywords: ゲノム / 放射線 / がん / 遺伝学 / 遺伝子

Outline of Annual Research Achievements

1980年以降広島大学にて治療を行った小児がん患者のうち、小児がんが治癒し、その後フォローアップされ成人に至り次世代の児を持ちえた28組中、同意が得られた15組および配偶者のゲノムについて解析した。神経芽腫6例、腎芽腫3例、肝芽腫1例、悪性リンパ腫2例、横紋筋肉腫1例、悪性胚細胞腫1例であり、化学療法を全例が、放射線療法を6例が受けていた。また、二次がんを発症した4例についても同意を得て、検討した。
1. 治療前後のゲノム解析:エクソーム解析：進行小児がん経験者6例の治療前と治療後の体細胞DNAのエクソーム解析を行ったところ、エクソン上に生じた変異が2、9、12、16，32、84個検出された。また、2例について、low depthにて全ゲノムシークエンスを治療前後で行い、全ゲノム上での変異の検出を試みたところ126、87個であった。また、二次がんを発症した2例も同様に治療前後と二次がん組織の全ゲノムシークエンスを施行したが、治療後は73と198でそのうち二次がんではさらに2,000個以上の変異を認めた。
2. 次世代のゲノム解析：小児がん経験者とその配偶者と児について3組のエクソーム解析を行った。3組とも、化学療法と放射線療法がおこなわれた症例で１．で認められた変異部位を中心に解析したところ、2歳時に治療を受けた1例では84個中3個、3歳時に治療を受けた1例で12個中1個が児に伝搬している可能性が示唆された。前者は、患者の治療年齢、治療内容とくに腹部の放射線療法が影響している可能性が示唆され、今後症例を重ねて検討することとした。また、二次がん症例については１．の2例に加えて二次がんを発症した体細胞ゲノムを2例のエクソーム解析を行って検討したが、二次がん発症例に共通の部位、あるいは変異のパターンは同定できず、今後さらに症例を追加して検討することが必要と考えられた。

Research Products

• [Journal Article] Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates (2016)
  • Author(s): Honda S, Minato M, Suzuki H, Fujiyoshi M, Miyagi H, Haruta M, Kaneko Y, Hatanaka KC, Hiyama E, Kamijo T, Okada T, Taketomi A
  • Journal Title: Cancer Science Volume: in press Pages: in press
  • DOI: 10.1111/cas.12928
  • Peer Reviewed / Open Access
• [Journal Article] Circulating free DNA as non-invasive diagnostic biomarker for childhood solid tumors (2015)
  • Author(s): Kurihara S, Ueda Y, Onitake Y, Sueda T, Ohta E, Morihara N, Hirano S, Irisuna F, Hiyama E
  • Journal Title: Journal of Pediatric Surgery Volume: 50 Pages: 2094-2097
  • DOI: 10.1016/j.jpedsurg.2015.08.033.
  • Peer Reviewed / Open Access
• [Journal Article] Mortality and morbidity in primarily resected hepatoblastomas in Japan: Experience of the JPLT (Japanese Study Group for Pediatric Liver Tumor) trials (2015)
  • Author(s): Hiyama E, Hishiki T, Watanabe K, Ida K, Yano M, Oue T, Iehara T, Hoshino K, Koh K, Tanaka Y, Kurihara S, Ueda Y, Onitake Y
  • Journal Title: Journal of Pediatric Surgery Volume: 50 Pages: 2098-2101
  • DOI: 10.1016/j.jpedsurg.2015.08.035.
  • Peer Reviewed / Open Access
• [Journal Article] Direct Lipido-Metabolomics of Single Floating Cells for Analysis of Circulating Tumor Cells by Live Single-cell Mass Spectrometry (2015)
  • Author(s): Hiyama E, Ali A, Amer S, Harada T, Shimamoto K, Furushima R, Abouleila Y, Emara S, Masujima T
  • Journal Title: Analytical Sciences Volume: 1 Pages: 1215-1217
  • DOI: 10.2116/analsci.31.1215.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model (2015)
  • Author(s): Czauderna P, Haeberle B, Hiyama E, Rangaswami A, Krailo M, Maibach R, Rinaldi E, Feng Y, Aronson D, Malogolowkin M, Yoshimura K, Leuschner I, Lopez-Terrada D, Hishiki T, Perilongo G, von Schweinitz D, Schmid I, Watanabe K, Derosa M, Meyers R
  • Journal Title: European Journal of Cancer Volume: 1 Pages: 92-101
  • DOI: 10.1016/j.ejca.2015.09.023.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Exome sequencing of hepatoblastoma identifies biological signatures and protential therapeutic targets (2016)
  • Author(s): Hiyama E
  • Organizer: International Pediatric Liver Tumor Symposium
  • Place of Presentation: Texas, USA
  • Year and Date: 2016-02-25 – 2016-02-26
  • Int'l Joint Research
• [Presentation] 小児肝がんに対するゲノム解析と国際共同臨床試験へのアプローチ (2015)
  • Author(s): 檜山 英三
  • Organizer: 第53回日本癌治療学会学術集会
  • Place of Presentation: 京都市
  • Year and Date: 2015-10-29 – 2015-10-31
• [Presentation] Prediction of prognosis by preoperative chemotherapy response in hepatoblastoma patients treated by JPLT-2 protocol (2015)
  • Author(s): Hiyama E, Hishiki T, Ida K, Watanabe K, Oue T, Yano M, Hoshino K, Iehara T, Koh K, Tanaka Y, Kurihara S, Ueda Y
  • Organizer: SIOP 2015
  • Place of Presentation: Cape Town, South Africa
  • Year and Date: 2015-10-08 – 2015-10-11
  • Int'l Joint Research
• [Presentation] Integrated exome analysis in childhood hepatoblastoma: Biological approach for molecular targeting (2015)
  • Author(s): Hiyama E, Kurihara S, Onitake Y, Ueda Y, Morihara N, Fukuba I, Komatsu R
  • Organizer: SIOP 2015
  • Place of Presentation: Cape Town, South Africa
  • Year and Date: 2015-10-08 – 2015-10-11
  • Int'l Joint Research
• [Presentation] Changes in the clinical features of neuroblastoma 10 years after the cessation of mass screening in Japan (2015)
  • Author(s): Yoneda A, tajiri T, Hiyama E, Iehara T, Hishiki T, Sugito K, Hayashi Y, Maeda K, Yonekura T
  • Organizer: SIOP 2015
  • Place of Presentation: Cape Town, South Africa
  • Year and Date: 2015-10-08 – 2015-10-11
  • Int'l Joint Research
• [Presentation] Congenital hepatoblastoma in JPLT-2 study (2015)
  • Author(s): Watanabe K, Hishiki T, Ida K, Oue T, Yano M, Hoshino K, Iehara T, Koh K, Tanaka Y, Hiyama E
  • Organizer: SIOP 2015
  • Place of Presentation: Cape Town, South Africa
  • Year and Date: 2015-10-08 – 2015-10-11
  • Int'l Joint Research
• [Presentation] Survival and late effects in the risk-stratified hepatoblastoma patients treated by JPLT-2 protocol (2015)
  • Author(s): Hiyama E, Kurihara S, Ueda Y, Hishiki T, Ida K, Iehara T, Oue T, Yano M, Watanabe K, Hoshino K, Ko K, Tanaka Y
  • Organizer: 2015 ASCO Annual Meeting
  • Place of Presentation: Chicago, U.S.A
  • Year and Date: 2015-05-29 – 2015-06-02
  • Int'l Joint Research
• [Presentation] Circulating free DNA as non-invasive diagnostic biomarker for childhood solid tumors (2015)
  • Author(s): Kurihara S, Ueda Y, Onitake Y, Sueda T, Ohta E, Morihara N, Hirano S, Irisuna F, Hiyama E
  • Organizer: 48th Annual Meeting of the Pacific Association of Pediatric Surgeons
  • Place of Presentation: Jeju, South Kore
  • Year and Date: 2015-05-17 – 2015-05-21
  • Int'l Joint Research
• [Presentation] Mortality and morbidity in primarily resected hepatoblastomas in Japan: experience of JPLT (Japanese study group for pediatric liver tumor) trials (2015)
  • Author(s): Hiyama E, Hishiki T, Watanabe K, Ida K, Yano M, Oue T, Iehara T, Hoshino K, Koh K, Tanaka Y, Kurihara S, Ueda Y, Onitake Y
  • Organizer: 48th Annual Meeting of the Pacific Association of Pediatric Surgeons
  • Place of Presentation: Jeju, South Kore
  • Year and Date: 2015-05-17 – 2015-05-21
  • Int'l Joint Research