Investigation of molecular pathology based on quantitative evaluation of intratumor heterogeneity in hepatocellular carcinoma

Research Project

Project/Area Number	19K07722
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 50020:Tumor diagnostics and therapeutics-related
Research Institution	Kindai University
Principal Investigator	Sakai Kazuko 近畿大学, 医学部, 講師 (20580559)
Co-Investigator(Kenkyū-buntansha)	西尾和人近畿大学, 医学部, 教授 (10208134) 海堀昌樹関西医科大学, 医学部, 教授 (30333199)
Project Period (FY)	2019-04-01 – 2022-03-31
Project Status	Completed (Fiscal Year 2021)
Budget Amount *help	¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords	肝細胞癌 / 腫瘍内不均一性 / 遺伝子異常 / 肝細胞がん / 遺伝子変異 / コピー数変化
Outline of Research at the Start	本研究では、肝細胞がんの腫瘍内のコピー数異常とBアレル頻度データから腫瘍内不均一性を評価し、腫瘍内不均一性の多寡による肝細胞がんの臨床的、病理組織学的特徴との関連から、腫瘍内不均一性の病態を明らかにする。
Outline of Final Research Achievements	Tumor heterogeneity based on copy number variations is associated with the evolution of cancer and its clinical grade. Clonal composition (CC) represents the number of clones based on the distribution of B-allele frequency (BAF) obtained from a genome-wide single nucleotide polymorphism (SNP) array. A higher CC number represents a high degree of heterogeneity. Somatic mutations, total transcriptome, and copy number variation were analyzed in patients with resectable HCC. The samples were classified the heterogeneous tumors as poly-CC (n=26) and the homogeneous tumors as mono-CC (n=8). The patients with poly-CC had a higher rate of early recurrence and a significantly shorter recurrence-free survival period than the mono-CC patients. A transcriptome analysis showed that cell cycle-related pathways were enriched in the poly-CC tumors compared with the mono-CC tumors. Poly-CC HCC is highly proliferative and has a high risk of early recurrence.
Academic Significance and Societal Importance of the Research Achievements	肝細胞癌における腫瘍の不均一性を数値化し、腫瘍内不均一性の高いpoly-CC腫瘍が術後再発と関連することを明らかにした。コピー数変動及びB-アレル頻度に基づいたClonal composition数による腫瘍内不均一性の指標は、細胞周期関連経路の活性化を伴う増殖性の特徴と関連し、肝細胞癌の分子病態の新たな知見が見いだされた。