Investigation for hidden cancer predisposition in pediatric cancer

• Project/Area Number: 19K22608
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: The University of Tokyo (2020); National Center for Child Health and Development (2019)
• Principal Investigator: Kato Motohiro 東京大学, 医学部附属病院, 教授 (40708690)
• Co-Investigator(Kenkyū-buntansha): 樋渡 光輝 東京大学, 医学部附属病院, 講師 (40597126)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 癌

Outline of Research at the Start

本研究は、「小児がん発症者のがん細胞にみられる遺伝子変異は、体細胞変異（獲得された後天的な変異）と考えられていたものでも、一定の頻度で、正常細胞にわずかに存在する生殖細胞系列細胞バリアントに由来する」という仮説のもとに、鋭敏なゲノム解析手法を用いることで小児がん患者における"隠れたがん素因"の頻度を探索し、小児がんの発症における遺伝的背景についての理解を深めることを目的とする。

Outline of Final Research Achievements

Intensive analysis of the SMARCB1 gene in malignant rhabdoid tumors (MRT) revealed eight of 16 patients with germline genetic variants. Three patients had mosaicism of the variants, which conventional methods might overlook. The prevalence of cancer predisposition in MRT may thus be higher than previously reported.
We next focused on prevalence of germline variants of GATA2 and SAMD9/9L in hematologic disorder with monosomy 7. A total of 25 patients were analyzed, and seven patients with a germline pathogenic GATA2 variant were found. For SAMD9/9L screening, next-generation sequencing was used to detect low-abundance variants and found four novel germline variants. Functional analysis revealed that three out of the four variants showed functional abnormality. GATA2 and SAMD9/9L were sequenced in 25 patients with pediatric hematologic disorders associated with -7, and 40% of them were found to have some pathogenic germline variants in the three genes.

Academic Significance and Societal Importance of the Research Achievements

これらの研究により、小児がんの発症や臨床経過において遺伝的な背景の役割が重要であることが確認された。

Research Products

• [Int'l Joint Research] St. Jude小児病院(米国)
• [Journal Article] Prevalence of germline GATA2 and SAMD9/9L variants in paediatric haematological disorders with monosomy 7 (2020)
  • Author(s): Yoshida, M. Tanase-Nakao, K. Shima, H. Shirai, R. Yoshida, K. Osumi, T. Deguchi, T. Mori, M. Arakawa, Y. Takagi, M. Miyamura, T. Sakaguchi, K. Toyoda, H. Ishida, H. Sakata, N. Imamura, T. Kawahara, Y. Morimoto, A. Koike, T. Yagasaki, H. Ito, S. Tomizawa, D. Kiyokawa, N. Narumi, S. Kato, M.
  • Journal Title: British Journal of Haematology Volume: 191 Issue: 5 Pages: 835-843
  • DOI: 10.1111/bjh.17006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High prevalence of SMARCB1 constitutional abnormalities including mosaicism in malignant rhabdoid tumors (2020)
  • Author(s): Shirai Ryota、Osumi Tomoo、Terashima Keita、et al
  • Journal Title: European Journal of Human Genetics Volume: 未刊 Issue: 8 Pages: 26-26
  • DOI: 10.1038/s41431-020-0614-z
  • Peer Reviewed / Open Access
• [Presentation] NUDT15 variants confer high incidence of secondary malignancies of ALL in children (2019)
  • Author(s): 吉田仁典ら
  • Organizer: 第61回日本小児血液・がん学会学術集会