Molecular pathology of EGFR-mutated lung adenocarcinoma

• Project/Area Number: 18K15086
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Yokohama City University
• Principal Investigator: MATSUMURA Mai 横浜市立大学, 医学部, 助教 (50812997)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: EGFR変異肺腺癌 / MUC21 / 微小乳頭状亜型 / 全エクソーム解析 / バイオインフォマティクス解析 / 肺癌 / 肺腺癌 / EGFR変異

Outline of Final Research Achievements

Our recent study demonstrated that malignant grade of EGFR-mutated lung adenocarcinoma (LADC) was determined by micropapillary (mPAP) element. I revealed that MUC21 was related to mPAP element of EGFR-mutated LADCs, and the tumors expressed MUC21 protein had poor prognosis. To uncover the potential molecular basis of mPAP element, I investigated somatic mutations specific to mPAP element in EGFR-mutated LADC. mPAP and other elements were separately collected from frozen tissue sections of EGFR-mutated LADC by the laser capture microdissection system and were subjected to whole exomes sequencing analyses. Through bioinformatics analysis, somatic mutations which was cofirmed by sanger-sequencing specific to mPAP elements were identified. Finally, I made “Highly malignant EGFR-mutated LADCs gene panel”. These gene mutations might be related to the highly malignant activity of mPAP element.

Academic Significance and Societal Importance of the Research Achievements

これまで肺がん臨床の現場で分子治療標的となる遺伝子変異は、腫瘍発生に関わるドライバー変異であった。我々が作成した「高悪性度EGFR肺腺癌パネル」に含まれる後発変異が治療標的となれば、EGFRチロシンキナーゼ阻害薬（EGFR-TKI）との併用により、腫瘍の悪性化や薬剤耐性化の阻止に役立つ可能性がある。

Research Products

• [Journal Article] The nonsmokers’ and smokers’ pathways in lung adenocarcinoma: Histological progression and molecular bases (2021)
  • Author(s): Okudela Koji、Matsumura Mai、Arai Hiromasa、Woo Tetsukan
  • Journal Title: Cancer Science Volume: 112 Issue: 9 Pages: 3411-3418
  • DOI: 10.1111/cas.15031
  • Peer Reviewed / Open Access
• [Journal Article] Frequent DYRK2 gene amplification in micropapillary element of lung adenocarcinoma - an implication in progression in EGFR-mutated lung adenocarcinoma. (2021)
  • Author(s): Koike C, Okudela K, Matsumura M, Mitsui H, Suzuki T, Arai H, Kataoka T, Ishikawa Y, Umeda S, Tateishi Y, Ohashi
  • Journal Title: Histology and Histopathology Volume: 36(3) Pages: 305-315
  • Peer Reviewed
• [Journal Article] A lung tumor with features of salivary duct carcinoma (2021)
  • Author(s): Sato Keisuke、Matsumura Mai、Anzai Yoko、Arai Hiromasa、Sekiya Motoki、Sugiyama Misaki、Kataoka Toshiaki、Koike Chihiro、Ohashi Kenichi、Okudela Koji
  • Journal Title: Pathology International Volume: 71 Issue: 4 Pages: 284-286
  • DOI: 10.1111/pin.13072
  • Peer Reviewed
• [Journal Article] Frequent DYRK2 gene amplification in micropapillary element of lung adenocarcinoma - an implication in progression in EGFR-mutated lung adenocarcinoma (2020)
  • Author(s): Chihiro Koike, Koji Okudela, Mai Matsumura, Hideaki Mitsui, Takehisa Suzuki, Hiromasa Arai, Toshiaki Kataoka, Yoshihiro Ishikawa, Shigeaki Umeda, Yoko Tateishi, Kenichi Ohashi
  • Journal Title: Histology and Histopathology . Volume: Online ahead of print.
  • Peer Reviewed
• [Journal Article] Unilateral upper lung-field pulmonary fibrosis radiologically consistent with pleuroparenchymal fibroelastosis after thoracic surgery: Clinical and radiological courses with autopsy findings (2020)
  • Author(s): Sekine Akimasa、Satoh Hiroaki、Takemura Tamiko、Matsumura Mai、Okudela Koji、Iwasawa Tae、Okabayashi Hiroko、Ikeda Satoshi、Yamakawa Hideaki、Oda Tsuneyuki、Okuda Ryo、Kitamura Hideya、Baba Tomohisa、Komatsu Shigeru、Hagiwara Eri、Ogura Takashi
  • Journal Title: Respiratory Investigation Volume: 58 Issue: 6 Pages: 448-456
  • DOI: 10.1016/j.resinv.2020.05.001
  • Peer Reviewed
• [Journal Article] An NRAS mutation in primary malignant melanoma of the lung: a case report (2020)
  • Author(s): Hibiya Takashi、Tanaka Meiro、Matsumura Mai、Aoki Ayako、Ikegami Tadashi、Okudela Koji、Kawano Naomi、Ohashi Kenichi
  • Journal Title: Diagnostic Pathology Volume: 15 Issue: 1
  • DOI: 10.1186/s13000-020-0928-8
  • Peer Reviewed
• [Journal Article] Miliary Lung Metastases from Genital Large Cell Neuroendocrine Carcinomas (2019)
  • Author(s): Sekine Akimasa、Satoh Makiko、Okudela Koji、Matsumura Mai、Morishita Yukio、Minami Yuko、Hayashihara Kenji、Saito Takefumi、Iwasawa Tae、Ogura Takashi
  • Journal Title: Internal Medicine Volume: 58 Issue: 8 Pages: 1127-1130
  • DOI: 10.2169/internalmedicine.1220-18
  • NAID: 130007632761
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-04-15
  • Peer Reviewed
• [Journal Article] Specific expression of MUC21 in micropapillary elements of lung adenocarcinomas -Implications for the progression of EGFR-mutated lung adenocarcinomas, (2019)
  • Author(s): Matsumura M, Okudela K, Nakashima Y, Mitsui H, Denda-Nagai K, Suzuki T, Arai H, Umeda S, Tateishi Y, Koike C, Kataoka T, Irimura T, Ohashi.
  • Journal Title: PLoS One Volume: 14 Issue: 4 Pages: e0215237-e0215237
  • DOI: 10.1371/journal.pone.0215237
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unique expression profiles of mucin proteins in interstitial pneumonia-associated lung adenocarcinomas. (2019)
  • Author(s): Kataoka T1, Okudela K2, Nakashima Y1, Mitsui H1, Matsumura M1, Umeda S1, Arai H3,4, Baba T5, Suzuki T1, Koike C1, Tateishi Y1, Tajiri M4, Takemura T6, Ogura T5, Masuda M3, Ohashi K1.
  • Journal Title: Histol Histopathol Volume: 34(11) Pages: 1243-1254
  • Peer Reviewed / Open Access
• [Journal Article] A subpopulation of airway epithelial cells that express hepatocyte nuclear factor 4α - its implication in the development of non-terminal respiratory unit-type lung adenocarcinoma. (2019)
  • Author(s): Okudela K1, Arai H2, Kitamura H3, Baba T3, Mitsui H4, Suzuki T4, Sugiyama M5, Honda E5, Matsumura M4, Takemura T5, Kataoka T4, Koike C4, Tateshi Y4, Tajiri M2, Ogura T3, Ohashi K4.
  • Journal Title: Histol Histopathol Volume: 34(11) Pages: 1217-1227
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary melanocytic nevus ? A case report with a mutation analysis of common driver oncogenes (2019)
  • Author(s): Tanaka Meiro、Matsumura Mai、Okudela Koji、Mitsui Hideaki、Tateishi Yoko、Umeda Shigeaki、Suzuki Takehisa、Koike Chihiro、Kataoka Toshiaki、Kawano Naomi、Kojima Yui、Osawa Hiroyuki、Ohashi Kenichi
  • Journal Title: Pathology International Volume: 69 Issue: 11 Pages: 667-671
  • DOI: 10.1111/pin.12850
  • Peer Reviewed
• [Journal Article] A subpopulation of airway epithelial cells that express hepatocyte nuclear factor 4α - its implication in the development of non-terminal respiratory unit-type lung adenocarcinoma (2019)
  • Author(s): Okudela K, Arai H, Kitamura H, Baba T, Mitsui H, Suzuki T, Sugiyama M, Honda E, Matsumura M, Takemura T, Kataoka T, Koike C, Tateshi Y, Tajiri M, Ogura T, Ohashi K
  • Journal Title: Histology and histopathology Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Secondary pulmonary alveolar proteinosis predominant in the transplanted lung in patients with idiopathic interstitial pneumonia: an autopsy case (2018)
  • Author(s): Ikeda Satoshi、Sekine Akimasa、Baba Tomohisa、Katano Takuma、Yamakawa Hideaki、Oda Tsuneyuki、Iwasawa Tae、Matsumura Mai、Takemura Tamiko、Ogura Takashi
  • Journal Title: Journal of Thoracic Disease Volume: 10 Issue: 5 Pages: E351-E354
  • DOI: 10.21037/jtd.2018.04.49
  • Peer Reviewed / Open Access
• [Journal Article] A molecular pathological study of four cases of ciliated muconodular papillary tumors of the lung. (2018)
  • Author(s): Kataoka T, Okudela K, Matsumura M, Mitsui H, Suzuki T, Koike C, Sawazumi T, Umeda S, Tateishi Y, Yamanaka S, Ishikawa Y, Arai H, Tajiri M, Ohashi K.
  • Journal Title: Pathol Int Volume: 68 Issue: 6 Pages: 353-358
  • DOI: 10.1111/pin.12664
  • Peer Reviewed / Open Access
• [Presentation] Identification of somatic mutations promoting progression of EGFR-mutated adenocarcinoma (2021)
  • Author(s): 松村舞依
  • Organizer: 第110回日本病理学会総会
• [Presentation] Pathological verification of Oncomine Dx Target Test in non-small cell lung carcinoma (2021)
  • Author(s): 松村舞依
  • Organizer: 第62回日本肺癌学会学術集会
• [Presentation] クライオバイオプシーによる間質性肺炎の診断 びまん性肺疾患の病理診断におけるクライオ生検の現状. (2021)
  • Author(s): 松村 舞依
  • Organizer: 第39回日本画像医学会
• [Presentation] 非小細胞肺がんにおけるオンコマインDx 検査の現状. (2020)
  • Author(s): 松村 舞依
  • Organizer: 第109 回日本病理学会総会
• [Presentation] びまん性肺疾患の病理診断におけるクライオ生検の現状 (2020)
  • Author(s): 松村舞依
  • Organizer: 第39回日本画像医学会
• [Presentation] EGFR肺腺癌の微小乳頭状組織亜型に特徴的な体細胞遺伝子変異の解明 (2019)
  • Author(s): Mai Matsumura, Koji Okudela, Chihiro Koike, Jun Nakabayashi, Hideaki Mitsui, Takehisa Suzuki, Toshiaki Kataoka, Shigeaki Umeda, Yoko Tateishi, Hiromasa Arai, Kenichi Ohashi
  • Organizer: 第108回日本病理学会総会
• [Presentation] Somatic mutations specific to micropapillary element in EGFR-mutated lung adenocarcinoma (2019)
  • Author(s): Mai Matsumura, Koji Okudela, Chihiro Koike, Jun Nakabayashi, Hideaki Mitsui, Takehisa Suzuki, Toshiaki Kataoka, Shigeaki Umeda, Yoko Tateishi, Hiromasa Arai, Kenichi Ohashi
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] びまん性肺疾患の病理診断におけるクライオ生検と外科的生検の比較 (2019)
  • Author(s): 松村 舞依
  • Organizer: 第38回日本画像医学会
• [Presentation] Relationship between MUC21 expression and glycosylation status in EGFR-mutated lung adenocarcinoma (2018)
  • Author(s): Mai Matsumura, Koji Okudela, Hideaki Mitsui, Kaori Denda-Nagai, Hiromasa Arai, Shigeaki Umeda, Yoko Tateishi, Shoji Yamanaka, Tatsuro Irimura, Kenichi Ohashi
  • Organizer: 第107回日本病理学会総会