Mutations in polymerase ε (POLE) confer favorable prognosis and outcomes in various cancer types, but their role in non-small cell lung cancer (NSCLC) is unknown. Utilizing the data of 513 patients with adenocarcinoma (LUAD) and 497 patients with squamous cell carcinoma (LUSC) from The Cancer Genome Atlas (TCGA) cohort, we tested the prognostic value of POLE mutations and programmed cell death ligand 1 (PD-L1) expression in the two main subtypes of NSCLC. POLE mutation is a favorable biomarker for the improved overall survival (OS) of the LUSC patients (P = 0.033, 28 mutant vs. 469 wildtype patients), but not that of the LUAD patients (P = 0.12, 31 mutant vs. 482 wildtype patients). POLE-mutant LUAD patients with high expression of PD-L1 (Mut-High, n = 6) exhibited improved OS (P = 0.024) when compared to POLE-mutant patients with low PD-L1 expression (Mut-Low, n = 24) and other patients without POLE mutation (n = 476). This benefit was not due to the high content of the tumor infiltrating lymphocytes. Instead, the antitumor immune response was activated in Mut-High patients so that these patients were likely responding more effectively to immuno-oncology (IO) treatments; whereas genes involved with metabolic pathways were enriched in Mut-Low group, which may cause the decreased OS of these patients. Our study sheds light on the molecular basis of NSCLC and adds to our understanding of responses to chemotherapy and IO therapy.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0832-y) contains supplementary material, which is available to authorized users.
<div>Abstract<p>When recruited to promoters, histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) activate transcription by opening chromatin through H3K4 methylation. Here, we report that <i>KMT2</i> mutations occur frequently in non–small cell lung cancer (NSCLC) and are associated with high mutation loads and poor survival. KMT2C regulated DNA damage responses (DDR) through direct recruitment to DNA damage sites by Ago2 and small noncoding DNA damage response RNA, where it mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. Furthermore, by disrupting homologous recombination (HR)–mediated DNA repair, <i>KMT2C/D</i> mutations sensitized NSCLC to Poly(ADP-ribose) polymerase inhibitors (PARPi), whose efficacy is unclear in NSCLC due to low <i>BRCA1/2</i> mutation rates. These results demonstrate a novel, transcription-independent role of KMT2C in DDR and identify high-frequency <i>KMT2C/D</i> mutations as much-needed biomarkers for PARPi therapies in NSCLC and other cancers with infrequent <i>BRCA1/2</i> mutations.</p>Significance:<p>This study uncovers a critical role for KMT2C in DDR via direct recruitment to DNA damage sites, identifying high-frequency <i>KMT2C/D</i> mutations as biomarkers for response to PARP inhibition in cancer.</p></div>
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