Aberrant histone modification patterns of tumor-related gene promoter as a new biomarker for renal cell carcinoma

• Project/Area Number: 18K09150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Keio University
• Principal Investigator: SHINOJIMA Toshiaki 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (60306777)
• Co-Investigator(Kenkyū-buntansha): 水野 隆一 慶應義塾大学, 医学部(信濃町), 准教授 (60383824)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腎細胞癌 / エピジェネティクス / 遺伝子変異 / 腫瘍免疫 / エピジェネシス / ヒストン修飾 / クロマチンリモデリング / PBRM1 / CD68 / HIF-2α / 癌関連遺伝子

Outline of Final Research Achievements

Recent high-throughput profiling of renal cell carcinomas (RCC) has identified a recurrent mutation including chromatin regulators, such as genes involved in the chromatin remodeling or in histone modifications. In this study, using a chromatin immunoprecipitation assay, we found that there was a significant difference in active modification patterns in the promoter region of HIF2A, which is a potent oncogenic driver in RCC. The mutation in chromatin regulators, did not affect the pathological tumor grade nor T stage; however, it revealed to be an independent significant factor that affect overall and progression free survival of RCC patients. Moreover, some molecular markers of immune cells was significantly decreased in the tumor samples harboring the mutation, suggesting the interaction of chromatin regulators and tumor-immune system.

Academic Significance and Societal Importance of the Research Achievements

手術時に転移を認めない症例でも、従来の病理診断にエピジェネティクス関連遺伝子変異の有無を加味することは、フォローアップスケジュールの決定や術後補助療法の必要性の判断などに有用な可能性があり、臨床での応用が期待される。また、転移や再発のリスクが高い非転移性腎細胞癌の術後補助療法に、腫瘍免疫を制御する薬物療法が有効である可能性が示唆されたことは、今後の発展が大いに期待される知見である。

Research Products

• [Journal Article] Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients (2019)
  • Author(s): Kimiharu Takamatsu, Ryuichi Mizuno, Nobuyuki Tanaka, Toshikazu Takeda, Shinya Morita, Kazuhiro Matsumoto, Takeo Kosaka, Toshiaki Shinojima, Eiji Kikuchi, Hiroshi Asanuma, Masafumi Oyama, Shuji Mikami, Mototsugu Oya
  • Journal Title: Int J Clin Oncol Volume: 24 Issue: 9 Pages: 1069-1074
  • DOI: 10.1007/s10147-019-01459-1
  • Peer Reviewed / Open Access
• [Journal Article] Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration?Time Curve for Metastatic Renal-Cell Carcinoma (2019)
  • Author(s): Miura Yuji、Imamura Chiyo K.、Uchino Keita、Kishida Takeshi、Matsubara Nobuaki、Shinojima Toshiaki、Kondo Keiichi、Hongo Fumiya、Yoshimura Kenichi、Tanigawara Yusuke、Takano Toshimi
  • Journal Title: Clinical Genitourinary Cancer Volume: 17 Issue: 1 Pages: e1-e11
  • DOI: 10.1016/j.clgc.2018.09.015
  • Peer Reviewed
• [Journal Article] Prognostic Value of Baseline Serum C-Reactive Protein Level in Intermediate-Risk Group Patients With Metastatic Renal-Cell Carcinoma Treated by First-Line Vascular Endothelial Growth Factor-Targeted Therapy. (2018)
  • Author(s): Takamatsu K1, Mizuno R2, Omura M1, Morita S1, Matsumoto K1, Shinoda K1, Kosaka T1, Takeda T1, Shinojima T1, Kikuchi E1, Asanuma H1, Oyama M3, Mikami S4, Oya M1.
  • Journal Title: Clin Genitourin Cancer Volume: 16（4） Issue: 4 Pages: e927-e933
  • DOI: 10.1016/j.clgc.2018.03.012
  • Peer Reviewed / Open Access
• [Presentation] Predictors of first line systemic therapy for metastatic renal cell carcinoma in IMDC favorable risk patients (2020)
  • Author(s): Mizuno R, Takamatsu K, Tanaka N, Hayakawa N, Kosaka T, Kikuchi E, Oya M
  • Organizer: ASCO Annual Meeting
  • Int'l Joint Research
• [Presentation] The change of serum C-reactive protein levels during molecular-targeted treatments could predict the response to anti-PD-1 treatment in metastatic renal cell carcinoma patients (2020)
  • Author(s): Takamatsu K, Mizuno R, Hayakawa N, Tanaka N, Kosaka T, Kikuchi E, Oya M
  • Organizer: ASCO Annual Meeting
  • Int'l Joint Research
• [Presentation] 転移性腎細胞癌に対するニボルマブの効果予測因子の検討 (2018)
  • Author(s): 108.高松公晴、水野隆一、田中伸之、武田利和、森田伸也、松本一宏、小坂威雄、篠島利明、菊地栄次、浅沼宏、三上修治、大家基嗣
  • Organizer: 第56回日本癌治療学会学術集会