Diversity of U1 Small Nuclear RNAs and Diagnostic Methods for Their Mutations.

Journal: Cancer science
Published Date: May 27, 2025

Abstract

U1 small nuclear RNA (snRNA) mutations are recurrent non-coding alterations found in various malignancies, yet their identification has proven challenging due to their repetitive nature. We characterized the complex interindividual diversity and genomic architecture of U1 snRNA loci using sequencing data and a pangenome reference. Our analysis uncovered copy number variations and the diversity of single-nucleotide variants in regions not predicted to have significant functional impact. Compared to traditional linear reference-based analyses for mutations, the pangenome graph demonstrated the best accuracy, successfully identifying previously undetectable mutations. This underscores the utility of pangenome graph references for cancer genome research, particularly in repetitive and highly diverse genomic regions. Additionally, we developed mutation detection methods employing targeted capture sequencing, rapid quantitative polymerase chain reaction, and a machine learning approach based on splicing patterns, all exhibiting high precision in identifying U1 snRNA mutations. Our findings elucidate the structural complexity of U1 snRNA loci and establish robust methodologies for precise mutation detection in these regions.

Authors

  • Takuma Nakashima
    Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo City, Japan.
  • Tsubasa Miyauchi
    Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo City, Japan.
  • Ryota Takeuchi
    In Vitro Diagnostics Business, KYORIN Pharmaceutical Co., Ltd, Tokyo, Japan.
  • Yuriko Sugihara
    Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo City, Japan.
  • Yusuke Funakoshi
    Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo City, Japan.
  • Fumiharu Ohka
    Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
  • Sachi Maeda
    Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
  • Junko Hirato
    Department of Pathology, Public Tomioka General Hospital, Tomioka, Japan.
  • Takako Yoshioka
    Department of Pathology, National Center for Child Health and Development, Setagaya, Japan.
  • Hajime Okita
    Division of Diagnostic Pathology, Keio University School of Medicine, Minato City, Japan.
  • Yoshitaka Narita
    Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan.
  • Yonehiro Kanemura
    Kansai Molecular Diagnosis Network for CNS Tumors, Osaka, 540-0006, Japan.
  • Yasuhiro Kojima
    Laboratory of Computational Life Science, National Cancer Center Research Institute, Tokyo, Japan.
  • Yuko Watanabe
    Department of Pediatric Oncology, National Cancer Center Hospital, Chuo City, Japan.
  • Ryuta Saito
    Department of Neurology (S.N., T.M., Y.T., K.T., N.Y., H.K., M.A.), Department of Multiple Sclerosis Therapeutics (T.M.), Department of Neurosurgery (R.S., T.T.), and Department of Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University; Department of Virology 1 (K.N., M.S.), Laboratory of Neurovirology, National Institute of Infectious Diseases; Department of Neurology (I.N.), Tohoku Medical and Pharmaceutical University, Sendai; and Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Japan.
  • Hiromichi Suzuki
    Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo City, Japan.

Keywords

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