Functional analysis of lung cancers with RASA1 mutations

• Project/Area Number: 16K08674
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Juntendo University
• Principal Investigator: Hayashi Takuo 順天堂大学, 医学部, 准教授 (70569128)
• Co-Investigator(Kenkyū-buntansha): 齋藤 剛 順天堂大学, 医学部, 准教授 (80439736)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺癌 / 肺腺癌 / 病理学 / トランスレーショナルリサーチ

Outline of Final Research Achievements

Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RASA1-mutated cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040u;M GSK1120212).
To better understand the histopathological features of these tumor, we compared histological features of 613 surgically resected lung adenocarcinomas in never or light smokers between each mitogenetic driver alteration. 79% of cases in our archive had mitogenic driver alterations; METex14 was the sixth most frequently altered gene (13 tumors, 2.1%), and other alterations included mutations of EGFR (59%), KRAS (6.0%), ERBB2 (2.5%), BRAF (2.5%), MAP2K1 (1.1%), fusions of ALK (2.6%), RET (1.0%), ROS1 (1.4%), and NRG1 (0.5%)。

Academic Significance and Societal Importance of the Research Achievements

RASA1/NF1遺伝子変異陽性細胞はMEK阻害薬であるGSK1120212により、増殖が抑制されることが明らかとなり、GSK1120201がRASA1/NF1遺伝子変異陽性症例に対して新規治療薬となる可能性を示した。一方、TCGAのデータセットでは、RASA1の遺伝子変異は2.2%と報告されており、本件研究のコホートにおいても10～30症例程度RASA1遺伝子変異を有する症例を同定できると仮定していたが、非喫煙者・軽喫煙者ではRASA1遺伝子変異陽性の患者は同定されなかった。KRAS遺伝子変異と同様に人種間で変異率に差異がある可能性が示唆された。

Research Products

• [Journal Article] Non-small cell lung carcinoma with diffuse co-expression of thyroid transcription factor-1 and ΔNp63/p40. (2018)
  • Author(s): Hayashi T, Takamochi K, Yanai Y, Mitani K, Tomita H, Mogushi K, Suehara Y, Takahashi F, Suzuki K, Saito T, Yao T. Non-small cell lung carcinoma with diffuse co-expression of thyroid transcription factor-1 and ΔNp63/p40.
  • Journal Title: Hum Pathol Volume: 78 Pages: 79-88
  • Peer Reviewed
• [Presentation] 病理検体に影響を与える検体処理因子 (2019)
  • Author(s): 林 大久生
  • Organizer: 第29回日本肺癌学会学術集会
  • Invited
• [Presentation] Clinicopathological characteristics of lung adenocarcinoma with EGFR compound mutations. (2019)
  • Author(s): 林 大久生, 高阪 真路, 高持 一矢, 原貴恵子, 高橋 史行, 末原 義之, 齋藤 剛, 鈴木 健司, 間野 博行, 八尾 隆史
  • Organizer: United States and Canadian Academy of Pathology (USCAP) 108th Annual Meeting
  • Int'l Joint Research
• [Presentation] 肺腺癌におけるゲノム・病理組織学の統合的解析：ERBB2, METex14, BRAF, MAP2K1陽性腺癌の臨床病理学的特徴 (2018)
  • Author(s): 林 大久生, 高阪 真路, 高持 一矢, 末原 義之, 茂櫛 薫, 高橋 史行, 齋藤 剛, 鈴木 健司, 間野 博行, 八尾 隆史
  • Organizer: 第107回日本病理学会総会
• [Presentation] Integrated histologic and genomic analyses of lung adenocarcinoma in never or light smokes identify unique histological characteristics of MET exon 14 skipping-positive tumors (2018)
  • Author(s): 林 大久生, 高阪 真路, 高持 一矢, 末原 義之, 茂櫛 薫, 高橋 史行, 齋藤 剛1, 鈴木 健司, 間野 博行7, 八尾 隆史
  • Organizer: 第29回日本肺癌学会学術集会
• [Book] PrecisionMedicine 特集「がんゲノム医療の基礎と臨床」各論 病理診断医の立場から見たがんクリニカルシークエンス検査 -MSK-IMPACT日本導入の経験から- (2019)
  • Author(s): 林 大久生
  • Total Pages: 102
  • Publisher: 北隆館