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"Miyakoshi, Junko"
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More life-size zoo : lion, hippopotamus, polar bear and more : an all-new actual-size animal encyclopedia
See life-size photographs of various animals, with fold-out pages and charts and sidebars of interesting facts.
Book
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.
RNA splicing dysregulation is a hallmark of cancer but remains poorly understood in solid tumors. Here, the authors map splicing patterns in lung adenocarcinoma, uncover a CMTR2-mutant subtype, and show its vulnerability to splicing modulators and immunotherapy.
Journal Article