Mechanistic insight into malignant transformation and therapeutic strategies based on the comparative multi-omics analysis of primary and recurrent gliomas

2017 Fiscal Year Final Research Report

• Project/Area Number: 26293321
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kumamoto University (2017); The University of Tokyo (2014-2016)
• Principal Investigator: Mukasa Akitake 熊本大学, 大学院生命科学研究部(医), 教授 (90463869)
• Co-Investigator(Kenkyū-buntansha): 田中 將太 東京大学, 医学部附属病院, 助教 (80643725)
• Co-Investigator(Renkei-kenkyūsha): SAITO Kuniaki 杏林大学, 医学部, 助教 (50446564)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Keywords: 悪性神経膠腫 / ゲノム / エピゲノム / 腫瘍内多様性 / 治療抵抗性

Outline of Final Research Achievements

To understand the changes of the molecular profile during tumor progression and to develop a proper treatment strategy, multi “omics” analysis was performed in approximately 122 gliomas that includes 22 paired samples of primary and recurrent tumors with exome sequencing and RNA-sequencing, as well as Infinium 450K methylation chip. The integrated bioinformatics analysis revealed that a large proportion of recurrent tumors had markedly different set of mutations and showed branched evolution pattern. Some malignantly transformed diffuse astrocytomas previously treated by temozolomide acquired numerous de novo mutations accompanying mutations in mismatch repair genes and showed a “hypermutator phenotype”. Genome-wide DNA methylation analysis revealed characteristic DNA demethylation during malignant progression in a subset diffuse astrocytomas. Interestingly, we found that most loci that were demethylated during malignant progression were located outside of CpG islands.

Free Research Field

脳腫瘍