Investigating the molecular pathogenesis of brain tumors through integrative whole-genome and multi-omics approaches

The increasing use of next-generation sequencing has enabled comprehensive genomic profiling of various primary brain tumors. As a result, classifications based on genetic alterations are gradually being incorporated into diagnostic and clinical practice. In many brain tumors, the presence or absence of specific genetic abnormalities now informs prognosis and allows molecular stratification of patients. However, the development of targeted therapies based on these findings remains limited.

We conducted a comprehensive genetic analysis of 757 cases of lower-grade glioma (LGG; WHO Grade II and III), a type of malignant brain tumor (Suzuki H et al., Nature Genetics, 47(5):458–468, 2015). This landmark study was the first to reveal that LGGs can be classified into three distinct groups based on mutational patterns. Our findings have been widely recognized and incorporated into the WHO Classification of Tumors of the Central Nervous System in both 2016 and 2021.

In a separate study, we reanalyzed whole-genome data from 341 medulloblastoma cases and discovered recurrent mutations in U1 small nuclear RNA (U1 snRNA) (Suzuki H et al., Nature, 574(7780):707–711, 2019). Due to the multiple genomic loci of U1 snRNA, these mutations had previously evaded detection with conventional methods. Further whole-genome analyses of various cancers, including chronic lymphocytic leukemia, hepatocellular carcinoma, and pancreatic cancer, revealed that U1 snRNA mutations are also present in these malignancies (Shimin S, Hiromichi S. Nature, 574(7780):712–716, 2019). This was the first report to implicate small nuclear RNA in tumorigenesis and contributed to updates in the 2021 WHO classification of brain tumors.

Through these studies, we aim to uncover novel molecular mechanisms underlying brain tumor development by leveraging whole-genome analysis. Our ultimate goal is to identify new therapeutic targets and pave the way for the development of innovative treatments for patients with malignant brain tumors.

G-CARD project

G-CARD (Genome research in CAncers and Rare Diseases) is a national initiative launched in Japan in 2021, based on the Implementation Plan for Whole Genome Analysis. The project aims to advance the clinical application of whole-genome sequencing (WGS) in cancer and rare diseases. As part of this initiative, our laboratory leads the brain tumor research group within the rare cancer division, with a particular focus on WGS of brain tumors.

To date, we have conducted whole-genome sequencing on over 400 brain tumor cases and are actively analyzing these data. By integrating WGS with other sequencing data from these cases, we are working toward the clinical implementation of whole-genome sequencing. Our research aims to identify novel genetic alterations and establish refined molecular classifications of brain tumors.

Through this work, we hope to improve diagnostic accuracy and contribute critical data that will pave the way for personalized medicine in the treatment of brain tumors.