免疫遺伝子発現シグネチャーによる食道がん術前化学療法の奏効予測

• Project/Area Number: 19K09206
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 藤田 征志 国立研究開発法人理化学研究所, 生命医科学研究センター, 客員研究員 (80564749)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 食道がん

Outline of Research at the Start

Stage II-III食道癌に対する日本の標準治療は術前化学療法であるが、その奏効率は必ずしも高くない。術前化学療法の効果を事前に予測できれば、治療方針の選択にとって有用である。本研究の目的は、食道癌化学療法の奏効予測のための免疫学的バイオマーカーを開発することである。このために化学療法前の生検組織についてRNA-Seq解析を実施し、各種の免疫遺伝子発現量や発現シグネチャーを、responder, non-responder間で比較する。機械学習の特徴抽出法を用いて免疫学的バイオマーカーを構築し、公共データベースの食道癌発現プロファイルで再現性を検証する。

Outline of Annual Research Achievements

食道扁平上皮癌73症例のサンプルをご提供いただき、解析を行った。性別は男性60症例、女性13症例であった。術前化学療法の奏効性はResponder 54症例、Non-responder 19症例であった。
腫瘍組織を浸潤T細胞の多寡に基づいて、Hot, Coldの二群に分類した。具体的にはRNA-Seqで得られた遺伝子発現量から、Spranger et al, 2015のT細胞シグネチャー13遺伝子 (CD8A, ICOS, CXCL9, CXCL10, GZMK, IRF1, HLA-DOA, HLA-DOB, HLA-DMA, HLA-DMB, CCL2, CCL3, CCL4)の値を抽出し、これに階層的クラスタリング法を適用した。36症例がHot群、37症例がCold群に分類された。術前化学療法の奏効率はHotクラスにおいて86.1% (31/36)、Coldクラスにおいて62.2% (23/37)であり、オッズ比は3.71 (95%信頼区間1.07-15.10)、Fisher検定によるp値は0.032であり、統計学的に有意な差が認められた。性別との関連では、男性における奏効率が73.3% (44/60)、女性で76.9% (10/13)であり、統計的有意差は見られなかった。すなわち食道扁平上皮癌の腫瘍内微小環境、特に浸潤T細胞量が、術前化学療法の高い奏効率と関連することが確認された。今後の研究の展開としては、T細胞以外の免疫細胞と化学療法奏効性の関連を調べることが考えられる。

Research Products

• [Journal Article] Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations. (2020)
  • Author(s): Fujita M, Yamaguchi R, Hasegawa T, Shimada S, Arihiro K, Hayashi S, Maejima K, Nakano K, Fujimoto A, Ono A, Aikata H, Ueno M, Hayami S, Tanaka H, Miyano S, Yamaue H, Chayama K, Kakimi K, Tanaka S, Imoto S, Nakagawa H.
  • Journal Title: EBioMedicine Volume: 53 Pages: 102659-102659
  • DOI: 10.1016/j.ebiom.2020.102659
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Somatic mutation landscape reveals differential variability of cell-of-origin for primary liver cancer. (2020)
  • Author(s): Ha KH, Fujita M, Karkic R, Yang S, Xue R, Zhang C, Bai F, Zhang N, Hoshida Y, Polak P, Nakagawa H, Kim HG, and Lee HJ
  • Journal Title: Heliyon Volume: 6 Issue: 2 Pages: e03350-e03350
  • DOI: 10.1016/j.heliyon.2020.e03350
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive Analysis of Indels in Whole-genome Microsatellite Regions and Microsatellite Instability across 21 Cancer Types (2020)
  • Author(s): Fujimoto A*, Fujita M, Hasegawa T, Wong JH, Maejima K, Oku-Sasaki A, Nakano K, Shiraishi Y, Miyano S, Yamamoto G, Akagi K, Imoto S, and Nakagawa H
  • Journal Title: Genome Research Volume: 30 Issue: 3 Pages: 334-34
  • DOI: 10.1101/gr.255026.119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole genome sequencing analysis identifies recurrent structural alterations in esophageal squamous cell carcinoma (2020)
  • Author(s): Dutta Munmee、Nakagawa Hidewaki、Kato Hiroaki、Maejima Kazuhiro、Sasagawa Shota、Nakano Kaoru、Sasaki-Oku Aya、Fujimoto Akihiro、Mateos Ra?l Nicol?s、Patil Ashwini、Tanaka Hiroko、Miyano Satoru、Yasuda Takushi、Nakai Kenta、Fujita Masashi
  • Journal Title: PeerJ Volume: 8 Pages: e9294-e9294
  • DOI: 10.7717/peerj.9294
  • Peer Reviewed / Open Access
• [Journal Article] Tumor fibroblast growth factor receptor 4 level predicts the efficacy of Lenvatinib in patients with advanced hepatocellular carcinoma. (2020)
  • Author(s): Yamauchi M, Ono A, Ishikawa A, Kodama K, Uchikawa S, Hatooka H, Zhang P, Teraoka Y, Morio K, Fujino H, Nakahara T, Murakami E, Miki D, Kawaoka T, Tsuge M, Hiramatsu A, Imanura M, Hayes CN, Fujita M, Nakagawa H, Yusui W, Aikata H, and Chayama K.
  • Journal Title: Clin Transl Gastroenterology Volume: 11 Issue: 5 Pages: e00179-e00179
  • DOI: 10.14309/ctg.0000000000000179
  • Peer Reviewed
• [Journal Article] 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population (2019)
  • Author(s): Takata Ryo、Takahashi Atsushi、Fujita Masashi et al.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 4422-4422
  • DOI: 10.1038/s41467-019-12267-6
  • NAID: 120006731132
  • Peer Reviewed / Open Access
• [Journal Article] Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes (2019)
  • Author(s): Xue Ruidong、Chen Lu、Zhang Chong、Fujita Masashi et al.
  • Journal Title: Cancer Cell Volume: 35 Issue: 6 Pages: 932-947
  • DOI: 10.1016/j.ccell.2019.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas (2019)
  • Author(s): Mateos Raul N.、Nakagawa Hidewaki、Hirono Seiko、...、Fujita Masashi
  • Journal Title: Cancer Medicine Volume: 8 Issue: 10 Pages: 4565-4573
  • DOI: 10.1002/cam4.2340
  • Peer Reviewed / Open Access
• [Journal Article] eVIDENCE: a practical variant filtering for low-frequency variants detection in cell-free DNA (2019)
  • Author(s): Mizuno Kei、Akamatsu Shusuke、Sumiyoshi Takayuki、Wong Jing Hao、Fujita Masashi et al.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 15017-15017
  • DOI: 10.1038/s41598-019-51459-4
  • NAID: 120006734882
  • Peer Reviewed / Open Access
• [Journal Article] Integrated exome and RNA sequencing of dedifferentiated liposarcoma (2019)
  • Author(s): Hirata Makoto、Matsubara Daisuke (21th) etc
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41467-019-13286-z
  • Peer Reviewed / Open Access / Int'l Joint Research