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

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.

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Publication Details

Journal
Nature Communications
Published
2025-11-06
DOI
https://doi.org/10.1038/s41467-025-64821-0
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
1.61
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article

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

Ryuji Hamamoto, Hiroyoshi Nishikawa, Shun‐ichi Watanabe, Kouya Shiraishi et al.
2 citations
Nature Communications
RNA Research and Splicing
1.61
article

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

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

Abstract

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.

Nature CommunicationsVol. 16(1)
Tohoku University (JP), Keio University (JP), Kyoto University (JP), Kawasaki Municipal Hospital (JP), National Cancer Center Hospital East (JP), National Cancer Research Institute (GB)
Openalex Percentile: Top 14%
RNA Research and Splicing
1.61
DOIOpen Access PDFOpenAlex
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