Pharmacogenomic analysis of biomarker that predict adverse events associated with 5-fluorouracil

• Project/Area Number: 15K10128
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Tohoku University
• Principal Investigator: Ohnuma Shinobu 東北大学, 大学病院, 助教 (70451565)
• Co-Investigator(Kenkyū-buntansha): 内藤 剛 東北大学, 医学系研究科, 准教授 (50291258)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: DPYD / MTHFR / OPRT / TYMS / 5-FU / splicing / 遺伝子多型 / DPD / 有害事象 / 胃癌 / 大腸癌 / ABC transporter

Outline of Final Research Achievements

The aim of this study was to investigate the association between 5-fluorouracil (5-FU)-related adverse events (AEs) in Japanese patients with gastrointestinal cancer treated with 5-FU and the patient genotypes DPYD, MTHFR, OPRT, and TYMS. Methods: Sequence analyses of 33 gene polymorphisms in four genes were performed using genomic DNA extracted from peripheral blood mononuclear cells of 88 patients with gastric (n = 30) or colorectal (n = 58) cancer. The associations between the incidence of AEs and each genotype were statistically analyzed. Results: The patients carrying any one of three DPYD SNPs (c.496A>G, c.1905+1G>A, and c.2303C>A) showed statistically significant associations with the incidence of AEs, especially fatigue, and the MTHFR SNP c.1298A>C was significantly associated with the incidence of neutropenia. Conclusion: These findings suggest that the genetic polymorphisms of DPYD and MTHFR may be predictive factors for the occurrence of severe 5-FU-related AEs.

Research Products

• [Journal Article] 腸管型ベーチェット病手術例の長期予後の検討 (2018)
  • Author(s): 伊勢 一郎、渡辺 和宏、長尾 宗紀, 大沼 忍, 唐澤 秀明, 鈴木 秀幸, 内藤 剛, 海野 倫
  • Journal Title: 日本大腸肛門病学会雑誌 Volume: 71 Pages: 133-138
  • NAID: 130006405046
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopy-Assisted Partial Duodenal Resection for Duodenal Adenoma in a Patient with Familial Adenomatous Polyposis (2018)
  • Author(s): Hirashima T, Ohnuma S, Karasawa H, Watanabe K, Imoto H, Aoki T, Kudoh K, Tanaka N, Nagao M, Musha H, Motoi F, Kamei T, Naitoh T, Unno M.
  • Journal Title: Gan To Kagaku Ryoho Volume: 45 Pages: 518-520
  • Peer Reviewed
• [Journal Article] Multidisciplinary Treatment for Squamous Cell Carcinoma of the Anal Canal (2017)
  • Author(s): Karasawa H, Ohnuma S, Watanabe K, Tsuchiya T, Imoto H, Aoki T, Kudoh K, Tanaka N, Nagao M, Abe T, Musha H, Motoi F, Kamei T, Naitoh T, Unno M.
  • Journal Title: Gan To Kagaku Ryoho Volume: 44 Pages: 2009-2010
  • Peer Reviewed
• [Journal Article] A Case of Curatively Resected Ascending Colon Cancer with Ovarian Metastasis and Peritoneal Dissemination after Chemotherapy (2017)
  • Author(s): Mochizuki Y, Karasawa H, Shimodaira H, Ohnuma S, Watanabe K, Maeda S, Nagao M, Aoki T, Kudo K, Tanaka N, Musha H, Motoi F, Kamei T, Naitoh T, Unno M.
  • Journal Title: Gan To Kagaku Ryoho Volume: 44 Pages: 1711-1713
  • Peer Reviewed
• [Journal Article] A Case of Leiomyosarcoma of the Small Intestine with Intestinal Hemorrhage Due to Intraluminal Penetration (2017)
  • Author(s): Tsuchiya T, Tanaka N, Nagao M, Watanabe K, Imoto H, Ohnuma S, Musha H, Watanabe M, Murakami K, Fujishima F, Motoi F, Naitoh T, Unno M.
  • Journal Title: Gan To Kagaku Ryoho Volume: 44 Pages: 1068-1070
  • Peer Reviewed
• [Journal Article] microRNA-193a-3p is specifically down-regulated and acts as a tumor suppressor in BRAF-mutated colorectal cancer. (2017)
  • Author(s): Takahashi, H.，Takahashi, M.，Ohnuma, S.，Unno, M.，Yoshino, Y.，Ouchi, K.，Takahashi, S.，Yamada, Y.，Shimodaira, H.，Ishioka, C.:
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 723-727
  • DOI: 10.1186/s12885-017-3739-x
  • Peer Reviewed / Open Access
• [Journal Article] Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance-Linked ATP-Binding Cassette Transporter ABCG2. (2017)
  • Author(s): Murakami M, Ohnuma S, Fukuda M, Chufan EE, Kudoh K, Kanehara K, Sugisawa N, Ishida M, Naitoh T, Shibata H, Iwabuchi Y, Ambudkar SV, Unno M.
  • Journal Title: Drug Metab Dispos. Volume: 45 Issue: 11 Pages: 1166-1177
  • DOI: 10.1124/dmd.117.076000
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein-arginine deiminase 2 suppresses proliferation of colon cancer cells through protein citrullination. (2017)
  • Author(s): Funayama R, Taniguchi H, Mizuma M, Fujishima F, Kobayashi M, Ohnuma S, Unno M, Nakayama K.
  • Journal Title: Cancer Sci. Volume: 108 Issue: 4 Pages: 713-718
  • DOI: 10.1111/cas.13179
  • Peer Reviewed / Open Access
• [Journal Article] Successful Extended Surgery for Mucinous Cystadenocarcinoma of the Appendix with the Right Iliopsoas Muscle Invasion (2017)
  • Author(s): 金原 圭吾, 大沼 忍, 唐澤 秀明, 渡辺 和宏, 工藤 克昌, 石田 晶玄, 佐藤 聡子, 元井 冬彦, 内藤 剛, 海野 倫明
  • Journal Title: The Japanese Journal of Gastroenterological Surgery Volume: 50 Issue: 9 Pages: 754-761
  • DOI: 10.5833/jjgs.2016.0158
  • NAID: 130006088684
  • ISSN: 0386-9768, 1348-9372
  • Peer Reviewed / Open Access
• [Presentation] 家族性大腸腺腫症に対する腹腔鏡下大腸全摘術 (2017)
  • Author(s): 大沼 忍, 渡辺 和宏, 長尾 宗紀, 唐澤 秀明, 井本 博文, 青木 豪, 工藤 克昌, 田中 直樹, 武者 宏昭, 亀井 尚, 内藤 剛, 海野 倫明
  • Organizer: 第30回日本内視鏡外科学会総会（京都）
• [Presentation] 直腸神経内分泌腫瘍に対する手術症例の検討 (2017)
  • Author(s): 大沼 忍, 唐澤 秀明, 渡辺 和宏, 鈴木 秀幸, 井本 博文, 青木 豪, 工藤 克昌, 田中 直樹, 長尾 宗紀, 武者 宏昭, 内藤 剛, 海野 倫明
  • Organizer: 第72回日本大腸肛門病学会学術集会（福岡）
• [Presentation] SURGICAL TREATMENTS FOR PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSIS (FAP); A SINGLE-INSTITUTE EXPERIENCE (2017)
  • Author(s): Ohnuma S, Karasawa H, Watanabe K, Suzuki H, Imoto H, Aoki T, Kudoh K, Tanaka N, Nagao M, Musha H, Motoi F, Kamei T, Naitoh T, Unno M.
  • Organizer: IASGO World Congress (Lyon, France)
  • Int'l Joint Research
• [Presentation] 原発性小腸癌に対する化学療法の現況 (2017)
  • Author(s): 大沼 忍, 唐澤 秀明, 渡辺 和宏, 鈴木 秀幸, 井本 博文, 青木 豪, 工藤 克昌, 田中 直樹, 長尾 宗紀, 武者 宏昭, 元井 冬彦, 内藤 剛, 海野 倫明
  • Organizer: 第55回日本癌治療学会学術集会（横浜）
• [Presentation] 抗癌剤感受性の増強を目指したP-glycoproteinに対する新規抑制剤の開発 (2017)
  • Author(s): 杉沢 徳彦, 大沼 忍, 村上 恵, 海野 倫明
  • Organizer: 第76回日本癌学会学術総会（横浜）
• [Presentation] 規合成クルクミン誘導体における抗癌剤耐性ABCトランスポーターの抑制効果 (2017)
  • Author(s): 村上 恵, 大沼 忍, 工藤 克昌, 石田 晶玄, 岩渕 好治, 柴田 浩行, 林 洋毅, 元井 冬彦, 内藤 剛, 海野 倫明
  • Organizer: 第76回日本癌学会学術総会（横浜）
• [Presentation] Stage IV大腸癌の外科治療戦略 (2017)
  • Author(s): 大沼 忍, 唐澤 秀明, 渡辺 和宏, 工藤 克昌, 阿部 友哉, 長尾 宗紀, 武者 宏昭, 元井 冬彦, 内藤 剛, 海野 倫明
  • Organizer: 第72回日本消化器外科学会総会（金沢）
• [Presentation] 遠隔転移を有する大腸癌に対する外科治療戦略 (2017)
  • Author(s): 大沼 忍, 唐澤 秀明, 渡辺 和宏, 土屋 堯裕, 井本 博文, 青木 豪, 工藤 克昌, 石田 晶玄, 田中 直樹, 長尾 宗紀, 阿部 友哉, 武者 宏昭, 中川 圭, 林 洋毅, 森川 孝則, 元井 冬彦, 内藤 剛, 海野 倫明
  • Organizer: 第117回日本外科学会定期学術集会（横浜）
• [Presentation] 大腸癌up-to-date (2017)
  • Author(s): 大沼 忍
  • Organizer: 大腸癌東北Webセミナー（仙台）
  • Invited
• [Presentation] Single-nucleotide polymorphisms of DPYD predict adverse events associated with 5-fluorouracil in patients with gastrointestinal cancer (2015)
  • Author(s): Shinobu Ohnuma, Masahide Toshima, Koh Miura, Katsuyoshi Kudoh, Masaharu Ishida, Hiroaki Musha, Fuyuhiko Motoi, Takeshi Naitoh, Michiaki Unno
  • Organizer: ESMO-Asia
  • Place of Presentation: Singapore, Singapre
  • Year and Date: 2015-12-18
  • Int'l Joint Research