Comprehensive analysis of LINE-1 hypomethylation level aimed at the development of new treatments for esophageal cancer

• Project/Area Number: 23689061
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: BABA Yoshifumi 熊本大学, 大学院生命科学研究部, 講師 (20599708)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2011: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000)
• Keywords: LINE-1 / メチル化 / 予後因子 / エピジェネティクス / 食道癌 / Pyrosequence / pyrosequence

Research Abstract

Using more than 200 ESCC specimens,we quantified the LINE-1 methylation by utilizing the bisulfite pyrosequencing technology. LINE-1 hypomethylation in ESCC is associated with a shorter survival, thus suggesting that it has potential for use as a prognostic biomarker. Result of CGH array, LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6. In our cohort of 129 patients with ESCC, cases with CDK6-positive expression experienced worse clinical outcome compared with those with CDK6-negative expression, supporting the oncogenic role of CDK6 in ESCC. In addition, we found that the prognostic impact of LINE-1 hypomethylation might be attenuated by CDK6 expression. LINE-1 hypomethylation in ESCC might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as CDK6.

Research Products

• [Journal Article] LINE-1 Hypomethylation, DNA Copy Number Alterations, and CDK6 Amplification in Esophageal Squamous Cell Carcinoma. (2014)
  • Author(s): Y. Baba, M. Watanabe, A. Murata, H. Shigaki, K. Miyake, T. Ishimoto, M. Iwatsuki, S. Iwagami, N. Yoshida, E. Oki, K. Sakamaki, M. Nakao, and H. Baba.
  • Journal Title: Clin Cancer Res Volume: 20 Pages: 1114-1124
  • DOI: 10.1158/1078-0432.ccr-13-1645
  • Peer Reviewed
• [Journal Article] Clinical implications of the LINE-1 methylation levels in patients with gastrointestinal cancer. (2014)
  • Author(s): Baba Y, Murata A, Watanabe M, Baba H
  • Journal Title: Surg Today Volume: (Epub ahead of print) Pages: 1807-16
  • DOI: 10.1007/s00595-013-0763-6
  • Peer Reviewed
• [Journal Article] Clinical implications of the LINE-1 methylation levels in patients with gastrointestinal cancer. (2014)
  • Author(s): Baba Y, Murata A, Watanabe M, Baba H.
  • Journal Title: Surg Today Volume: In press
  • Peer Reviewed
• [Journal Article] Aberrant methylation of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer (2013)
  • Author(s): Suzuki M, Shiraishi K, Eguchi A, Ikeda K, Mori T, Yoshimoto K, Ohba Y, Ito Yamada T, Ito T, Baba Y, Baba H
  • Journal Title: ONCOLOGY REPORTS Volume: 29(4) Pages: 1308-1314
  • DOI: 10.3892/or.2013.2266
  • Peer Reviewed
• [Journal Article] LINE-1 Hypomethylation is Associated with a Poor Prognosis Among Patients with Curatively Resected Esophageal Squamous Cell Carcinoma (2013)
  • Author(s): Iwagami S, Baba Y, Watanabe M, Shigaki H, Miyake K, Ishimoto T, Iwatsuki M, Sakamaki K, Ohashi Y, Baba H
  • Journal Title: Annals of Surgery Volume: 257(3) Pages: 449-55
  • DOI: 10.1097/sla.0b013e31826d8602
  • Peer Reviewed
• [Journal Article] LINE-1 hypomethylation in gastric cancer, detected by bisulfite pyrosequencing, is associated with poor prognosis (2013)
  • Author(s): Shigaki H, Baba Y, et al.
  • Journal Title: Gastric Cancer Volume: in press Pages: 480-487
  • DOI: 10.1007/s10120-012-0209-7
  • NAID: 40019845213
  • Peer Reviewed
• [Journal Article] LINE-1 Hypomethylation in Noncancerous Esophageal Mucosae is Associated with Smoking History (2012)
  • Author(s): Shigaki H, Baba Y, Watanabe M, Iwagami S, Miyake K, Ishimoto T, Iwatsuki M, Baba H
  • Journal Title: Ann Surg Oncol Volume: 19(13) Pages: 4238-43
  • DOI: 10.1245/s10434-012-2488-y
  • Peer Reviewed
• [Journal Article] Pyrosequencing Assay to Measure LINE-1 Methylation Level in Esophageal Squamous Cell Carcinoma (2012)
  • Author(s): Iwagami S, Baba Y, Watanabe M, Shigaki H, Miyake K, Ida S, Nagai Y, Ishimoto T, Iwatsuki M, Sakamoto Y, Miyamoto Y, Baba H.
  • Journal Title: Annals of Surgical Oncology Volume: 19(8) Pages: 2726-32
  • DOI: 10.1245/s10434-011-2176-3
  • Peer Reviewed
• [Journal Article] LINE-1 Hypomethylation is Associated with a Poor Prognosis Among Patients with Curatively Resected Esophageal Squamous Cell Carcinoma (2012)
  • Author(s): Iwagami S, Baba Y, et al
  • Journal Title: Ann Surg Volume: (印刷中)(In press)
  • Peer Reviewed
• [Presentation] 同時性・異時性頭頚部癌を有する食道癌症例におけるLINE-1メチル化レベル (2013)
  • Author(s): 馬場祥史、渡邊雅之、吉田直矢、小澄敬祐、原田和人、村田飛鳥、岩上志朗、辛島龍一、石本崇胤、馬場秀夫
  • Organizer: 第65回日本気管食道学会総会ならびに学術講演会
  • Place of Presentation: 品川プリンスホテル(東京都)
  • Year and Date: 2013-11-01
• [Presentation] 食道扁平上皮癌におけるLINE-1低メチル化とDNAコピー数異常、CDK6増幅の関係 (2013)
  • Author(s): 馬場祥史、渡邊雅之、村田飛鳥、志垣博信、三宅慧輔、石本崇胤、岩槻政晃、岩上志朗、吉田直矢、馬場秀夫
  • Organizer: 第72回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2013-10-05
• [Presentation] 食道癌におけるLINE-1メチル化レベルとDNAコピー数異常の関係 (2013)
  • Author(s): 馬場祥史、渡邊雅之、村田飛鳥、志垣博信、岩上志朗、石本崇胤、岩槻政晃、吉田直矢、馬場秀夫
  • Organizer: 第24回日本消火器癌発生学会
  • Place of Presentation: 石河県立音楽堂
  • Year and Date: 2013-09-05
• [Presentation] Pyrosequence technologyを用いた食道癌のエピゲノム解析 (2013)
  • Author(s): 馬場祥史、渡邊雅之、村田飛鳥、志垣博信、岩上志朗、石本崇胤、岩槻政晃、吉田直矢、馬場秀夫
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: マリンメッセ福岡
  • Year and Date: 2013-04-12
• [Presentation] Relationship between LINE-1 methylation level, allelic imbalance and PIK3CA mutation in esophageal squamous cell carcinoma (2013)
  • Author(s): Baba Y, Watanabe M, Murata A, Shigaki H, Iwagami S, Iwatsuki M, Ishimoto T, Baba H
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: Walter E. Washington Convention Center(アメリカ・ワシントン)
  • Year and Date: 2013-04-09
• [Presentation] Prognostic significance of LINE-1 methylation level in esophageal squamous cell carcinoma (2012)
  • Author(s): 馬場祥史
  • Organizer: ASCO GI
  • Place of Presentation: Moscone West Building(アメリカ・サンフランシスコ)
  • Year and Date: 2012-01-19
• [Presentation] Prognostic significance of LINE-1 methylation level in esophageal squamous cell carcinoma (2012)
  • Author(s): 馬場祥史
  • Organizer: ASCO GI
  • Place of Presentation: アメリカ合衆国サンフランシスコMoscone West Building
  • Year and Date: 2012-01-19
• [Presentation] Prognostic significance of LINE-1 methylation level (2012)
  • Author(s): 馬場 祥史
  • Organizer: ASCO2012 (poster discussion)
  • Place of Presentation: Mc Cormick Place（アメリカ・シカゴ）
• [Presentation] 食道癌におけるLINE-1メチル化レベル-Prognosis and Epigenetic Field Defect- (2012)
  • Author(s): 馬場 祥史
  • Organizer: 第66回日本食道学会学術集会
  • Place of Presentation: 軽井沢プリンスホテルウエスト
• [Presentation] 上部消化管癌におけるLINE-1メチル化レベルのprognostic markerとしての意義 (2012)
  • Author(s): 馬場 祥史
  • Organizer: 第67回日本消化器外科学会
  • Place of Presentation: 富山県民会館
• [Presentation] 上部消化管癌におけるLINE-1メチル化レベルと予後の関係 (2012)
  • Author(s): 馬場 祥史
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市教育文化会館