Studies on cancer genomics to develop personalized therapy and medicine in breast cancer: Whole exome sequencing analysis of primary breast cancer and its metastatic tumor.

• Project/Area Number: 22310123
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical genome science
• Research Institution: National Cancer Center Japan
• Principal Investigator: HOSODA Fumie 独立行政法人国立がん研究センター, 研究所, ユニット長 (30219191)
• Co-Investigator(Renkei-kenkyūsha): SHIBATA Tatsuhiro 独立行政法人国立がん研究センター, 研究所, 分野長 (90311414) ; TOTOKI Yasushi 独立行政法人国立がん研究センター, 研究所, ユニット長 (10373333) ; TSUDA Hitoshi 防衛医科大学校, 病態病理学講座, 教授 (70217321)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2012: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2011: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2010: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 乳癌 / リンパ節転移 / エクソンシークエンス / 個別化医療 / 遺伝子変異 / ゲノム構造異常解析

Research Abstract

Metastasis is the main cause of therapeutic failure and death in cancer patients. A number of genetic alterations have been identified in primary breast tumors, but genetic changes particular to the metastatic tumors have not been well studied. To investigate critical genetic changes that occur during the metastatic process, we performed whole exome sequencing of 14 trio-specimens: the primary breast cancer, its metastatic lymph node tumor and matched non-cancerous tissue from the same patient by massively parallel sequencing. Comparing the three genomes, we identified a wide variety of somatic variations, 26-676 (median=46) mutations in the primary tumors and 8-1034 (median=37) mutations in the metastatic lymph node tumors. The differences of mutation rates (34 single nucleotide variations (SNVs) at the lowest to 1710 SNVs at the highest) in individual patients suggested that various processes of tumor development and distinct selective pressures are present within the tumor environment. We identified 132 and 189 recurrent mutations specific to the primary and lymph node tumors, respectively, and evaluated its significance with a statistical ranking method. Our findings will provide new insights for the mechanism of breast tumor metastasis and future personalized therapy and molecular medicine.

Research Products

• [Journal Article] Mouse Model for ROS1-Rearranged Lung Cancer. (2013)
  • Author(s): Arai Y, Totoki Y, Takahashi H, Nakamura H, Hama N, Kohno T, Tsuta K, Yoshida A, Asamura H, Mutoh M, Hosoda F, Tsuda H, Shibata T
  • Journal Title: PLoS One Volume: 8(2) Issue: 2 Pages: e56010-e56010
  • DOI: 10.1371/journal.pone.0056010
• [Journal Article] Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. (2012)
  • Author(s): Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, Aoki M, Hosono N, Kubo M, Miya F, Arai Y, Takahashi H, Shirakihara T, Nagasaki M, Shibuya T, Nakano K, Watanabe-Makino K, Tanaka H, Nakamura H, Kusuda J, Ojima H, Shimada K, Okusaka T, Ueno M, Shigekawa Y, Kawakami Y, Arihiro K, Ohdan H, Gotoh K, Ishikawa O, Ariizumi S, Yamamoto M, Yamada T, Chayama K, Kosuge T, Yamaue H, Kamatani N, Miyano S, Nakagama H, Nakamura Y, Tsunoda T, Shibata T, Nakagawa H
  • Journal Title: Nature Genetic Volume: 44 Issue: 7 Pages: 760-764
  • DOI: 10.1038/ng.2291
  • Peer Reviewed
• [Journal Article] High-resolution characterization of a hepatocellular carcinoma genome (2011)
  • Author(s): Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S, Tsutsumi S,Sonoda K, Totsuka H, Shirakihara T,Sakamoto H, Wang L, Ojima H, Shimada K, Kosuge T, Okusaka T, Kato K, Kusuda J, Yoshida T, Aburatani H & S h i b a t a T
  • Journal Title: Nat Genet Volume: 43(5) Issue: 5 Pages: 464-9
  • DOI: 10.1038/ng.804
  • Peer Reviewed
• [Journal Article] DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung. (2010)
  • Author(s): Shibata T, Kokubu A, Miyamoto M, Hosoda F, Gotoh M, Tsuta K, Asamura H, Matsuno Y, Kondo T, Imoto I, Inazawa J, Hirohashi S
  • Journal Title: Oncogene Volume: 29 Pages: 4671-4681
  • Peer Reviewed
• [Presentation] 乳がん原発巣とリンパ節転移巣における遺伝的変異の解析 (2012)
  • Author(s): 細田文恵、十時 泰、新井康仁、津田 均、 井本逸勢、稲澤譲治、大木 操、柴田龍弘
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2012-09-21
• [Presentation] Genetic variations in primary breast cancer and its metastatic tumor. (2012)
  • Author(s): Fumie Hosoda
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌市）
• [Presentation] Comparison of genetic alterations in primary breast cancer and its metastatic tumor. (2011)
  • Author(s): Hosoda F, Totoki Y, Arai Y, Tsuda H, Imoto I, Inazawa J, Ohki M, Shibata T
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2011-12-14
• [Presentation] Comparison of genetic alterations in primary breast cancer and its metastatic tumor (2011)
  • Author(s): Hosoda F, Totoki Y, et al
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2011-12-14
• [Presentation] F-box and leucine-repeat protein 17 (FBXL17)は新規のがん抑制遺伝子である (2010)
  • Author(s): 新井康仁、細田文恵、島 豊、中西幸浩、 柳原五吉、北林一生、大木 操、広橋説雄、 柴田龍弘
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2010-09-23
• [Presentation] 全ゲノムシークエンスによる肝癌のゲノム構造異常解析 (2010)
  • Author(s): 山本尚吾、十時 泰、薗田幸太郎、細田 文恵、白木原琢哉、辰野健二、柴田龍弘、油 谷浩幸
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2010-09-23
• [Presentation] F-box and leucine-repeat protein 17(FBXL17)は新規のがん抑制遺伝子である (2010)
  • Author(s): 新井康仁、細田文恵, ら
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2010-09-23
• [Remarks]
  • URL: http://www.ncc.go.jp/jp/nccri/divisions/19genom/index.html