Search for new prognostic markers and establishment of personalised treatment for pulmonary high-grade neuroendocrine carcinoma based on a new subtype classification

• Project/Area Number: 19K18213
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Kobe University
• Principal Investigator: Jimbo Naoe 神戸大学, 医学部附属病院, 特命助教 (00773772)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: POU2F3 / 小細胞癌 / LCNEC / 分子分類 / 神経内分泌癌 / tuft cell / 大細胞神経内分泌癌 / 肺高悪性度神経内分泌癌 / 混合型小細胞癌 / 混合型大細胞神経内分泌癌 / 肺癌 / 神経内分泌 / 亜型 / 予後マーカー

Outline of Research at the Start

肺癌において、小細胞癌と大細胞神経内分泌癌(以下LCNEC)を含む肺高悪性度神経内分泌癌の予後不良状態が続いている。小細胞癌とLCNECは完全に別個でなく、病理学的、臨床的、遺伝子学的に重なりが想定されており、遺伝子異常に基く亜型に再分類した上での新規予後マーカー創出が望まれる。本研究では、肺高悪性度神経内分泌癌を遺伝子異常に基き亜型に分類し、亜型ごとに、新規予後マーカーの探索を行う。これにより、肺高悪性度神経内分泌癌における適切な個別化治療を可能にし、肺高悪性度神経内分泌癌全体の予後を改善するとともに、新規マーカーが肺高悪性度内分泌癌の発生、転移、浸潤にどのように寄与しているか明らかにする。

Outline of Final Research Achievements

Immunostain-based molecular classification (ASCL1, NEUROD1, POU2F3, YAP1) was performed on small cell carcinoma and LCNEC and correlated with clinicopathological factors. POU2F3-positive small cell carcinoma and POU2F3-positive LCNEC showed overlapping in cytohistological features. Additionally, POU2F3-positive carcinoma showed significantly higher expression of TTF-1, neuroendocrine markers, and significantly lower expression of bcl-2 and c-kit. Furthermore, POU2F3-positive carcinoma had a significantly better prognosis than POU2F3-negative carcinoma. POU2F3-positive carcinoma have clinicopathological independence, therefore the identification of this particular type is important when considering optimal personalised treatment.

Academic Significance and Societal Importance of the Research Achievements

①分子分類(ASCL1, NEUROD1, POU2F3, YAP1)は、元来、小細胞癌において提唱された分類方法であったが、LCNECでも当てはめることができることが示唆されたほか、小細胞癌とともにLCNECと同時に検討したことで、POU2F3の独自性を見いだすことができた。②分子分類と形態の相関を見出したシリーズでの研究報告としては世界初であると考えられる。

Research Products

• [Journal Article] Insulinoma‐associated protein 1 is a prognostic biomarker in pulmonary high‐grade neuroendocrine carcinoma (2020)
  • Author(s): Minami Kazuhiro、Jimbo Naoe、Tanaka Yugo、Ogawa Hiroyuki、Hokka Daisuke、Nishio Wataru、Yoshimura Masahiro、Itoh Tomoo、Maniwa Yoshimasa
  • Journal Title: Journal of Surgical Oncology Volume: 1 Issue: 2 Pages: 1-11
  • DOI: 10.1002/jso.25960
  • Peer Reviewed / Open Access
• [Journal Article] Neuroendocrine marker staining pattern categorization of small‐sized pulmonary large cell neuroendocrine carcinoma (2019)
  • Author(s): Minami Kazuhiro、Tanaka Yugo、Ogawa Hiroyuki、Jimbo Naoe、Nishio Wataru、Yoshimura Masahiro、Itoh Tomoo、Maniwa Yoshimasa
  • Journal Title: Thoracic Cancer Volume: 10 Issue: 11 Pages: 2152-2160
  • DOI: 10.1111/1759-7714.13202
  • NAID: 120006764479
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of CD 133 and BCL-2 in non-small cell lung cancer with neuroendocrine differentiation after transformation in ALK rearrangement-positive adenocarcinoma. (2019)
  • Author(s): Koyama K, Katsurada N, Jimbo N, Tachihara M, Tamura D, Nakata K, Nagano T, Yamamoto M, Kamiryo H, Kobayashi K, Itoh T, Nishimura Y
  • Journal Title: Pathology international Volume: 69 Issue: 5 Pages: 294-299
  • DOI: 10.1111/pin.12782
  • Peer Reviewed