The elucidation of the mechanism of multi-step hepatocarcinogenesis via whole genome sequence and organoid culture technology

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08443
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kyoto University
• Principal Investigator: Takai Atsushi 京都大学, 医学研究科, 助教 (80760587)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 肝細胞癌

Outline of Final Research Achievements

In the current study, we demonstrated the genetic landscape of multistep carcinogenesis in NIN-HCCs through comprehensive genetic analysis with multiregional WGS. We found that well-differentiated HCC already bears various genetic aberrations including point mutations,not only point mutations but also STVs and hypermethylation of the TERT promoter region occurred as the trunk events in HCC, indicating that cellular immortalization by TERT aberration
could be the key driver event in the initiation step of hepatocarcinogenesis.In addition, in the progression phase of hepatocarcinogenesis, a particular tumor cell among the immortalized cellular population newly acquires several genetic aberrations involved in some oncogenic pathways and evolves from slow growing
tumor cells to rapid-growing malignant cells, resulting in the formation of an inner aggressive HCC nodule.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究により、肝発癌の初期にはTERT遺伝子異常が必須である一方で、肝癌の進行期には多様な遺伝子異常や分子経路の異常が関与することが分かった。本研究により、多段階発癌の分子生物学的メカニズムの一端が解明された。本研究成果を基盤として、TERTを標的とした分子標的治療や、症例によって異なる遺伝子異常をターゲットとしたオーダーメイドの分子標的治療の開発につながることが期待される。