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<p>RNA splicing dysregulation has emerged as a hallmark of cancer and a promising therapeutic target; however, its full landscape in human solid cancer remains poorly characterized. To address this, we perform alternative splicing analyses using RNA-sequencing data from 751 lung adenocarcinoma samples from our cohort integrated with 519 samples from The Cancer Genome Atlas. Visualization of splicing patterns using t-distributed stochastic neighbor embedding reveals substantial inter-tumor heterogeneity driven by distinct molecular subtypes and histological differentiation. We identify a unique molecular subtype associated with inactivating mutations in <i>CMTR2</i>, which encodes Cap-specific mRNA (nucleoside-2’-O-)-methyltransferase 2. <i>CMTR2</i> mutations are observed in 3.8% of cases and are predominantly truncating mutations, which form an isolated cluster within the splicing landscape. Intrinsic and CRISPR-Cas9-engineered <i>CMTR2</i> mutations disrupt alternative splicing and sensitize cancer cells to sulfonamide-based RNA splicing modulators and immune checkpoint blockade therapy. Retrospective patient data confirm the increased sensitivity of <i>CMTR2</i>-deficient tumors to immune checkpoint blockade therapy. These findings uncover a previously unrecognized RNA splicing deficiency in human cancers and define a molecular subtype of lung adenocarcinoma driven by RNA splicing dysregulation, suggesting targets for therapeutic intervention in lung cancer.</p>

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Mutation of CMTR2 in Lung Adenocarcinoma Alters RNA Alternative Splicing and Reveals Therapeutic Vulnerabilities

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月6日

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  • Shigenari Nukaga,
  • Kouya Shiraishi,
  • Kenta Hamabe,
  • Akifumi Mochizuki,
  • Yu Hamaguchi,
  • Emi Ogawa,
  • Nguyen Thai Le,
  • Yoko Shimada,
  • Hanako Ono,
  • Hitomi Nishinakamura,
  • Yoshihisa Kobayashi,
  • Junko Hamamoto,
  • Ayako Ui,
  • Mitsugu Araki,
  • Yukari Sagae,
  • Keiko Ohgino,
  • Kai Sugihara,
  • Satoshi Endo,
  • Jun Miyakoshi,
  • Yuichi Shiraishi,
  • Hiroyuki Yasuda,
  • Yasushi Okuno,
  • Tatsuya Yoshida,
  • Yasushi Goto,
  • Yuichiro Ohe,
  • Shun-Ichi Watanabe,
  • Yasushi Yatabe,
  • Hiroyoshi Nishikawa,
  • Ryuji Hamamoto,
  • Takashi Kohno,
  • Takashi Nakaoku

摘要

RNA splicing dysregulation has emerged as a hallmark of cancer and a promising therapeutic target; however, its full landscape in human solid cancer remains poorly characterized. To address this, we perform alternative splicing analyses using RNA-sequencing data from 751 lung adenocarcinoma samples from our cohort integrated with 519 samples from The Cancer Genome Atlas. Visualization of splicing patterns using t-distributed stochastic neighbor embedding reveals substantial inter-tumor heterogeneity driven by distinct molecular subtypes and histological differentiation. We identify a unique molecular subtype associated with inactivating mutations in CMTR2, which encodes Cap-specific mRNA (nucleoside-2’-O-)-methyltransferase 2. CMTR2 mutations are observed in 3.8% of cases and are predominantly truncating mutations, which form an isolated cluster within the splicing landscape. Intrinsic and CRISPR-Cas9-engineered CMTR2 mutations disrupt alternative splicing and sensitize cancer cells to sulfonamide-based RNA splicing modulators and immune checkpoint blockade therapy. Retrospective patient data confirm the increased sensitivity of CMTR2-deficient tumors to immune checkpoint blockade therapy. These findings uncover a previously unrecognized RNA splicing deficiency in human cancers and define a molecular subtype of lung adenocarcinoma driven by RNA splicing dysregulation, suggesting targets for therapeutic intervention in lung cancer.