Identification of novel driver genes by whole genome sequencing of early stage lung tumors

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H00545
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: National Cancer Center Japan
• Principal Investigator: Kohno Takashi 国立研究開発法人国立がん研究センター, 研究所, 分野長 (80280783)
• Co-Investigator(Kenkyū-buntansha): 鈴木 絢子 東京大学, 大学院新領域創成科学研究科, 准教授 (00770348)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 肺がん / ゲノム / 遺伝子 / 治療標的

Outline of Final Research Achievements

Based on genomic alterations in adenocarcinoma in situ and minimally invasive adenocarcinoma, the mechanism of early lung carcinogenesis was clarified (Haga et al, Nat Comm, 2023). Oncogene alterations were found to function in the formation of early lung tumors, and mutations in cancer suppressor genes were found to function in the malignant transformation of early tumors. Global DNA hypomethylation and associated copy number changes and large-scale structural changes were inferred to contribute to malignant transformation. Novel oncogenic mutations were found among RET gene mutations, and their activation and oncogenic potential were demonstrated to be suppressed by RET kinase inhibitors. In conclusion, point mutations in the RET gene contribute to carcinogenesis of multiple cancer types, including lung cancer, and are therapeutic target molecules.

Free Research Field

ゲノム生物学

Academic Significance and Societal Importance of the Research Achievements

世界的にも貴重な上皮内肺がん、微小浸潤腺がんのゲノム変化を明らかにすることで、これまで明らかにされていなかった早期肺腫瘍形成の分子機構が明らかになり、その成果を国際一流紙に報告することができた。この知見は今後の肺がん予防や早期発見・治療のための基盤情報となると期待される。また、がん遺伝子変化陰性例にみられるRET遺伝子変異が、がん原性変異であり、既存RET阻害薬の治療標的となることが明らかにされた。今後、コンパニオン検査への本情報の組み込みなどがんゲノム医療への実装が望まれる。