Expression analysis and search for novel molecular target of the fetal adenocarcinoma of the lung using a reverse phase protein array

• Project/Area Number: 18K15111
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: The University of Tokyo (2021); Kanagawa Cancer Center Research Institute (2018-2020)
• Principal Investigator: Suzuki Masaki 東京大学, 医学部附属病院, 助教 (00770108)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 高悪性度胎児型腺癌 / 胎児型腺癌 / 肺腺癌 / KMT2C / 高悪性度胎児型肺腺癌 / 胎児型肺腺癌 / 逆相蛋白質アレイ / 肺癌

Outline of Final Research Achievements

High-grade fetal adenocarcinoma of the lung (H-FLAC) is a rare variant of pulmonary adenocarcinoma. Although expression analysis using a reverse phase protein array (RPPA) has planned in this study, we performed RNA-seq analysis because of difficulty of RPPA analysis using formalin fixed paraffin embedded tissues. The RNA-seq analysis showed that KMT2C expression was significantly lower in H-FLACs compared to that in common type pulmonary adenocarcinomas. Immunohistochemical analysis also showed significantly lower levels of KMT2C in H-FLACs compared to that in common type adenocarcinomas. Some H-FLACs showed diffuse p53 expression or aberrant β-catenin nuclear localization. Therefore, it was suggested that KMT2C dysfunction are potentially associated with the biological features of H-FLACs.

Academic Significance and Societal Importance of the Research Achievements

高悪性度胎児型肺腺癌(H-FLAC)では通常型腺癌に比べてKMT2Cの発現が低下している症例が多いことが明らかとなり，KMT2Cの機能異常が高頻度に生じていることが示唆された．KMT2Cはヒストンメチル化酵素として機能しており，この機能異常に基づくエピゲノム異常がH-FLACの特徴的な組織形態や臨床病理学的特徴に寄与している可能性が考えられる．また，これまでCTNNB1変異やβ-cateninの異常集積はL-FLACの特徴とされてきたが，これらの所見はH-FLACにおいても低頻度にみられることが明らかとなった．

Research Products

• [Journal Article] Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component (2021)
  • Author(s): Masaki Suzuki, Rika Kasajima, Tomoyuki Yokose, Hiroyuki Ito, Eigo Shimizu, Seira Hatakeyama, Kazuaki Yokoyama, Rui Yamaguchi, Yoichi Furukawa, Satoru Miyano, Seiya Imoto, Emi Yoshioka, Kota Washimi, Yoichiro Okubo, Kae Kawachi, Shinya Sato, Yohei Miyagi
  • Journal Title: Translational Lung Cancer Research Volume: 10 Issue: 3 Pages: 1292-1304
  • DOI: 10.21037/tlcr-20-1158
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 高悪性度胎児型肺腺癌におけるKMT2C発現の解析 (2022)
  • Author(s): 鈴木理樹
  • Organizer: 第111回日本病理学会総会
• [Presentation] 全エクソーム解析による高悪性度胎児型肺腺癌の遺伝子異常の解明 (2019)
  • Author(s): 鈴木 理樹
  • Organizer: 第108回日本病理学会総会
• [Presentation] Whole-exome sequencing of high-grade fetal lung adenocarcinomas (2019)
  • Author(s): 鈴木 理樹
  • Organizer: 第16回日韓合同スライドカンファレンス
  • Int'l Joint Research