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Intrapulmonary metastases of non-small cell lung cancer promoted by a hotspot gain-of-function mutation in KMT2C

ABSTRACT: Cancer cells can spread from their original sites to both other organs and other sites within the same organs. One example of the latter is the intrapulmonary metastasis (IPM) of lung cancer, which is associated with poor prognosis but barely studied. In this study, we compared the genomic profiles of lung cancers with and without IPM and identified a hotspot mutation in KMT2C p.C391*, as an IPM-specific "driver" mutation. Using recently developed mouse models with single primary lung tumors, we demonstrated that KMT2C p.C391*, but not the loss of wild-type Kmt2c, promotes IPM in mice. Patients with IPM and mice with tumors harboring KMT2C p.C391* exhibited reduced alveolar macrophages and natural killer cells. Depleting these innate immune cell populations, mimicking the effects of KMT2C p.C391*, enhanced the survival and growth of tumor cells within the alveolar space. Mechanistically, KMT2C p.C391*, which lacks the C-terminal SET domain essential for H3K4 methyltransferase activity and gene activation, paradoxically represses gene expression. This repressive function appears to be mediated by SETDB1 and its downstream H3K9me3. And KMT2C p.C391* globally suppresses the expression of transposable elements (TEs), potentially facilitating immune evasion of tumor cells within the alveolar environment by reducing the interferon pathways. Our findings identify KMT2C p.C391* as a novel IPM-specific mutation with diagnostic potential and highlight the roles of TEs and innate immunity in IPM, offering promising avenues for clinical intervention.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE288169 | GEO | 2025/02/01

REPOSITORIES: GEO

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Intrapulmonary metastases of non-small cell lung cancer promoted by a hotspot gain-of-function mutation in KMT2C

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