Mutation of CMTR2 in Lung Adenocarcinoma Alters RNA Alternative Splicing and Reveals Therapeutic Vulnerabilities
- 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
2025-11-06
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.