Second-hit gene mutations for developing renal cell carcinoma in VHL disease

• Project/Area Number: 18K09169
• 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: Kochi University
• Principal Investigator: Karashima Takashi 高知大学, 教育研究部医療学系臨床医学部門, 准教授 (60304672)
• Co-Investigator(Kenkyū-buntansha): 執印 太郎 高知大学, 医学部附属病院, 特任教授 (70128601) ; 津田 雅之 高知大学, 教育研究部医療学系基礎医学部門, 准教授 (90406182)
• 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: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 腎癌 / VHL / PBRM1 / CRISPR/Cas9 / セカンド/サードヒット遺伝子変異 / 免疫不全 / セカンド/サードヒット遺伝子 / VHL遺伝子

Outline of Final Research Achievements

The purpose of the present study is to produce a VHL disease model mice capable of tumorigenesis by introducing a second / third hits gene mutations following the VHL gene mutation. No tumorigenicity was observed in VHL or PBRM1 alone or in VHL / PBRM1 double heterozygous mutant mice. However about 50% of PBRM1 heterozygous mutant mice died mainly at the 7th week after birth (3.5-23 weeks). A mouse developed diabetes insipidus. The cause might be immunodeficiency. On the other hand, VHL / PBRM1 double heterozygous mutant mice were very healthy. We considered that the PBRM1 mutation following the VHL mutation may have been positively triggered to maintain homeostasis.

Academic Significance and Societal Importance of the Research Achievements

臨床形態を表現するVHL病モデルマウスの製作に現時点では至っていないが、研究の過程において、新たなPBRM1の役割が示唆された。PBRM1は、クロマチンの調節に作用をし、成体では主に、脾臓、リンパ節、胸腺、下垂体に高発現している。このことからPBRM1は免疫システムにおいて重要な役割を担う可能性があり、本研究結果はあらたな疾患概念の礎になる可能性がある。