Identification and functional analysis of the gene(s) associated with endcrine therapy for breast cancer.

• Project/Area Number: 24300338
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnosis
• Research Institution: National Cancer Center Japan (2013-2014); Sapporo Medical University (2012)
• Principal Investigator: ZEMBUTSU HITOSHI 独立行政法人国立がん研究センター, 研究所, ユニット長 (90372820)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2014: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: タモキシフェン / 乳がん / 個別化医療 / 遺伝子機能解析 / C10orf11 / 個別化内分泌療法 / 薬剤感受性 / 内分泌治療 / ゲノム解析

Outline of Final Research Achievements

We observed strong association between rs10509373 in C10orf11 and clinical outcome of 240 patients treated with tamoxifen through genome-wide association study. To clarify the function of C10orf11, whose function is unknown, we carried out some assays for investigation of gene expression of C10orf11, the effect on cell growth and screening of the interacting protein. We did not observe the expression of this gene in normal human tissues except adrenal gland, nor its effect on the cell growth. However, C10orf11 was suggested to be related to the wnt signaling in breast cancer. Further analysis focusing on the relationship between wnt signaling and estrogen receptor would clarify the mechanism of regulation of sensitivity to tamoxifen.

Research Products

• [Journal Article] Pharmacogenomics toward personalized tamoxifen therapy for breast cancer. (2015)
  • Author(s): Zembutsu H
  • Journal Title: Pharmacogenomics. Volume: 16 Issue: 3 Pages: 287-296
  • DOI: 10.2217/pgs.14.171
  • Peer Reviewed
• [Journal Article] Precision Medicine for Cancer and Pharmacogenomics. (2015)
  • Author(s): Zembutsu H
  • Journal Title: 血液内科 Volume: 70 Pages: 527-532
  • NAID: 40020439691
• [Journal Article] Lymph node shape in computed tomography imaging as a predictor for axillary lymph node metastasis in patients with breast cancer. (2014)
  • Author(s): Kutomi G, Ohmura T, Zembutsu H et al
  • Journal Title: Exp Ther Med. Volume: 8 Issue: 2 Pages: 681-685
  • DOI: 10.3892/etm.2014.1787
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] VAV3 mediates resistance to breast cancer endocrine therapy. (2014)
  • Author(s): Aguilar H, Urruticoechea A,Zembutsu H,et al
  • Journal Title: Breast Cancer Res Volume: 16 Issue: 3
  • DOI: 10.1186/bcr3664
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance). (2014)
  • Author(s): Chhibber A, Mefford J, Zembutsu H et al
  • Journal Title: Pharmacogenomics J. Volume: 14 Issue: 4 Pages: 336-342
  • DOI: 10.1038/tpj.2014.2
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populatins (2014)
  • Author(s): Province MA, Goetz MP, Zembutsu H, et al
  • Journal Title: Clin Pharmacol Ther. Volume: 95 Issue: 2 Pages: 216-227
  • DOI: 10.1038/clpt.2013.186
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A genome-wide association study of chemotherapy-induced alopecia in breast cancer patients. (2013)
  • Author(s): Chung S,Low SK, Zembutsu H,et al
  • Journal Title: Breast Cancer Res. Volume: 15 Issue: 5
  • DOI: 10.1186/bcr3475
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Important and critical scientific aspects in pharmacogenomics analysis: lessons from controversial results of tamoxifen and CYP2D6 studies. (2013)
  • Author(s): Kiyotani K, Mushiroda T, Zembutsu H,et al
  • Journal Title: J Hum Genet Volume: 58 Issue: 6 Pages: 327-333
  • DOI: 10.1038/jhg.2013.39
  • Peer Reviewed
• [Journal Article] Genome-wide association study of chemotherapeutic agent-tnduced severe neutropenia/leucopenia for patients in Biobank Japan. (2013)
  • Author(s): Low SK, Chung S, Zembutsu H, et al.
  • Journal Title: Cancer Sci. Volume: 104 Issue: 8 Pages: 1074-1082
  • DOI: 10.1111/cas.12186
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 遺伝子解析による薬物反応性 有害事象 ゲノムワイド関連解析によるゲムシタビン副作用関連遺伝子の同定. (2013)
  • Author(s): 前佛 均, 清谷 一馬, 宇野 智子, 木村 康利, 莚田 泰誠, 光畑 直喜, 伊奈 志乃美, 鬼原 史, 山上 裕機, 平田 公一, 中村 祐輔
  • Journal Title: Surgery Frontier Volume: 20 Pages: 198-201
• [Journal Article] 遺伝子解析による薬物反応性 抗腫瘍効果 浸潤性膀胱癌に対する術前化学療法 感受性予測システムの構築 (2013)
  • Author(s): 加藤 陽一郎, 高田 亮, 岩崎 一洋, 小原 航, 藤岡 知昭, 前佛 均, 中村 祐輔
  • Journal Title: Surgery Frontier Volume: 20 Pages: 194-197
• [Journal Article] ゲノムワイド関連解析による疾病関連遺伝子の同定 子宮内膜症 (2013)
  • Author(s): 宇野 智子, 前佛 均, 中村 祐輔.
  • Journal Title: Surgery Frontier Volume: 20 Pages: 184-187
• [Journal Article] ゲノムワイド関連解析による疾病関連遺伝子の同定 ケロイド (2013)
  • Author(s): 中島 光子, 前佛 均.
  • Journal Title: Surgery Frontier Volume: 20 Pages: 178-183
• [Journal Article] Integration of cell line and clinical trial genome-wide analyses supports apolygenic architecture of Paclitaxel-induced sensory peripheral neurxDpathy. (2013)
  • Author(s): Wheeler HE, Gamazon ER, Zembutsu H, et al.
  • Journal Title: Clin Cancer Res. Volume: 19 Issue: 2 Pages: 491-499
  • DOI: 10.1158/1078-0432.ccr-12-2618
  • Peer Reviewed
• [Journal Article] ゲノムワイド関連解析によるジェムシタビン副作用関連遺伝子の同定 (2013)
  • Author(s): 前佛均, 清谷一馬, 宇野智子, 木村康利, 慈田泰誠, 光畑直喜, 伊奈志乃美, 鬼原史, 山上裕機, 平田公一, 中村祐輔
  • Journal Title: 胆と膵(0388-9408) Volume: 34 Pages: 143-148
  • Peer Reviewed
• [Journal Article] Genome-wide association meta-analysis identifies new endometriosis risk loci. (2012)
  • Author(s): Nyholt DR, Low SK, Zembutsu H, et al.
  • Journal Title: Nat Genet. Volume: 44 Issue: 12 Pages: 1355-1359
  • DOI: 10.1038/ng.2445
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies a genetic variant in the SIAH2 locus associated with (2012)
  • Author(s): Elgazzar S,
  • Journal Title: J Hum Genet Volume: 57 Issue: 12 Pages: 766-71
  • DOI: 10.1038/jhg.2012.108
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. (2012)
  • Author(s): Baldwin RM, Owzar K, Zembutsu H, et al.
  • Journal Title: Clin Cancer Res. Volume: 18 Issue: 18 Pages: 5099-5109
  • DOI: 10.1158/1078-0432.ccr-12-1590
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies SNP in DCC is associated with gallbladder cancer in the Japanese population. (2012)
  • Author(s): Cha PC, Zembutsu H, et al.
  • Journal Title: J Hum Genet. Volume: 57 Issue: 4 Pages: 235-237
  • DOI: 10.1038/jhg.2012.9
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy (2012)
  • Author(s): Kazuma Kiyotani*, Satoko Uno*, Taisei Mushiroda, Atsushi Takahashi, Michiaki Kubo, Naoki Mitsuhata, Shinomi Ina, Chikashi Kihara, Yasutoshi Kimura, Hiroki Yamaue, Koichi Hirata, Yusuke Nakamura, Hitoshi Zembutsu
  • Journal Title: Pharmacogenet Genomics Volume: 22 Issue: 4 Pages: 229-235
  • DOI: 10.1097/fpc.0b013e32834e9eba
  • Peer Reviewed
• [Journal Article] Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA. (2012)
  • Author(s): Low SK, Takahashi A, Cha PC, Zembutsu H, et al.
  • Journal Title: Hum Mol Genet. Volume: 21 Issue: 9 Pages: 2102-2110
  • DOI: 10.1093/hmg/dds020
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese (2011)
  • Author(s): K.Kiyotani, T.Mushiroda, T.Tsunoda, T.Morizono, N.Hosono, M.Kubo, Y.Tanigawara, CK.Imamura, DA.Flockhart, F.Aki, K.Hirata, Y.Takatsuka, M.Okazaki, S.Ohsumi, T.Yamakawa, M.Sasa, Y.Nakamura, H.Zembutsu
  • Journal Title: Human Molecular Genetics Volume: (オンライン出版済) Issue: 7 Pages: 1665-1672
  • DOI: 10.1093/hmg/ddr597
  • Peer Reviewed
• [Presentation] CYP2D6 genotypeとタモキシフェン治療反応性の関係を解明する多施設共同前向き研究 (2014)
  • Author(s): 前佛 均、中村 清吾、明石 定子、桑山 隆志、渡邊 知映、武井 寛幸、石川 孝、長谷川 善枝、リー スーチン、松方 絢美、松本 広志、九冨 五郎、中村 祐輔
  • Organizer: 日本人類遺伝学会 第59回大会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] CYP2D6 genotypeとタモキシフェン治療反応性の関係を解明する多施設共同前向き研究 (2014)
  • Author(s): 前佛 均、中村 清吾、明石 定子、桑山 隆志、渡邊 知映、武井 寛幸、石川 孝、長谷川 善枝、リー スーチン、松方 絢美、松本 広志、九冨 五郎、中村 祐輔
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 網羅的遺伝子発現解析による筋層浸潤性膀胱がんのオーダーメイド医療 (2014)
  • Author(s): 高田 亮、加藤 陽一郎、前佛 均、片桐 豊雅、角田 達彦、藤岡 知昭、中村 祐輔、小原 航
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] PGxによるタモキシフェン治療効果予測：CYP2D6研究から学ぶこと (2014)
  • Author(s): 清谷 一馬、莚田 泰誠、前佛 均、中村 祐輔
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Prospective Clinical Study to Clarify the Relationship between CYP2D6 Genotype and the Therapeutic Effects of Preoperative Tamoxifen Therapy (2013)
  • Author(s): Hitoshi Zembutsu, Seigo Nakamura, Sadako Akashi, Takashi Kuwayama, Tomoko Takamaru, Yusuke Nakamura et al
  • Organizer: 日本人類遺伝学会 第58回大会
  • Place of Presentation: 仙台
  • Year and Date: 2013-11-20 – 2013-11-23
• [Presentation] A replication study of a GWAS identified three genetic loci associated with clinical outcomes of patients with invasive breast cancer (2013)
  • Author(s): Goro Kutomi, Koichi Hirata, Kazuma Kiyotani, Taisei Mushiroda, Tatsuhiko Tsunoda, Fuminori Aki, Yuichi Takatsuka, Minoru Okazaki, Shozo Ohsumi, Takashi Yamakawa, Mitsunori Sasa, Yusuke Nakamura and Hitoshi Zembutsu
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03 – 2013-10-05
• [Presentation] A prospective study to examine the availability of the prediction system of Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer (2013)
  • Author(s): Yoichiro Kato, Hitoshi Zembutsu, Ryo Takata, Kazuhiro Iwasaki, Wataru Obara, Yusuke Nakamura, Tomoaki Fujioka
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03 – 2013-10-05
• [Presentation] Genome-wide association studies identify different susceptibility loci for various subtypes of epithelial ovarian cancer in the Japanese population (2013)
  • Author(s): Hitoshi Zembutsu, Pei-Chieng Cha, Akira Hirasawa, Atsushi Takahashi, Tomoko Akahane, Siew-Kee Low, Michiaki Kubo, Daisuke Aoki, Yusuke Nakamura
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03 – 2013-10-05
• [Presentation] A genome-wide association study (GWAS) of docetaxel-induced peripheral neuropathy in CALGB 90401 (Alliance) (2013)
  • Author(s): Daniel Louis Hertz, Kouros Owzar, Susan Halabi, William Kevin Kelly, Hitoshi Zembutsu, et al
  • Organizer: ASCO Annual Meeting
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2013-05-31 – 2013-06-04
• [Presentation] ゲノムワイド関連解析によるタモキシフェン反応性診断 (2013)
  • Author(s): 前佛 均, 平田 公一, 岡崎 稔, 安藝 史典, 高塚 雄一, 大住 省三, 山川 卓, 笹 三徳, 中村 祐輔
  • Organizer: 日本外科学会 第113回大会
  • Place of Presentation: 福岡
  • Year and Date: 2013-04-11 – 2013-04-13
• [Presentation] ゲノムワイド関連解析によるジエムザール副作用関連遺伝子の同定 (2012)
  • Author(s): 前佛均, 清谷一馬, 中村祐輔, et al.
  • Organizer: 日本人類遺伝学会第57回大会
  • Place of Presentation: 京王プラザホテル(東京都新宿区)
  • Year and Date: 2012-10-27
• [Presentation] ゲノムワイド関連解析による膵癌発症関連遺伝子およびジェムシタビン副作用関連遺伝子の同定 (2012)
  • Author(s): 前佛均, 口羽文, Siew-Kee Low Siew-Kee, et al.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市立教育文化会館
  • Year and Date: 2012-09-21
• [Presentation] 遺伝子発現プロファイルに基づく乳がん術前化学療法感受性予測システムの構築 (2012)
  • Author(s): 鈴木やすよ, 前佛均, 西舘敏彦, 植木知身, 九冨五郎, 高丸智子, 平田公一
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 2012-09-21
• [Presentation] 局所浸潤性膀胱癌に対するネオアジュバント療法感受性予測前向き試験 (2012)
  • Author(s): 加藤陽一郎, 前佛均, et al.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 2012-09-20
• [Presentation] 遺伝子診断による乳癌オーダーメイド医療 (2012)
  • Author(s): 前佛均, 平田公一, 安井寛, 神津英至, 和田卓郎
  • Organizer: 第3回日本プライマリ・ケア連合学会学術大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-09-02
• [Presentation] CYP2D6遺伝子多型によるTAM投与量調節治療 (2012)
  • Author(s): 笹三徳, 清谷一馬, 筵田泰誠, 今村知世, 谷川原佑介, 細野直哉, 前佛均, 中村祐輔
  • Organizer: 第20回日本乳癌学会総会
  • Place of Presentation: テトリアくまもと
  • Year and Date: 2012-06-28
• [Book] Tamoxifen Pharmacogenetics (2013)
  • Author(s): Hitoshi Zembutsu
  • Publisher: The McGraw-Hill Companies(in press)