Oncogenic Properties of the Antisense lncRNA <i>COMET</i> in <i>BRAF</i>- and <i>RET</i>-Driven Papillary Thyroid Carcinomas.

Abstract

<i>RET</i> rearrangements as well as <i>BRAF</i> and <i>RAS</i> mutations drive differential pathway activation in papillary thyroid carcinomas, leading to different tumor phenotypes and prognoses. Although The Cancer Genome Atlas Consortium has identified tumor subgroups based on protein-coding gene signatures, neither expression of long noncoding RNAs (lncRNA) nor their correlation with specific tumor-driving mutations and rearrangements have been systematically assessed. Here, we reanalyzed our RNA-sequencing data using a <i>de novo</i> discovery approach to identify lncRNAs and define tumor subtype-specific signatures of annotated lncRNAs. Among them, we identified <i>COMET</i> (Correlated-to-<i>MET</i>), a natural antisense transcript that was highly expressed in carcinomas harboring <i>BRAF</i> ^V600E mutation or <i>RET</i> gene rearrangements (i.e., <i>BRAF</i>-like tumors) and induced the downstream MAPK pathway. In papillary thyroid carcinomas, <i>COMET</i> was part of a coexpression network including different oncogenes belonging to the MAPK pathway, and its expression highly correlated with <i>MET</i> expression. Depletion of <i>COMET</i> resulted in reduced expression of genes within this network, including the <i>MET</i> oncogene. <i>COMET</i> repression inhibited viability and proliferation of tumor cells harboring <i>BRAF</i> ^V600E somatic mutation or <i>RET</i> oncogene rearrangement and dramatically reduced motility and invasiveness of tumor cells. Moreover, silencing <i>COMET</i> markedly increased sensitivity to vemurafenib, a common inhibitor of mutated B-raf. Collectively, our results suggest <i>COMET</i> as a new target to improve drug-based cancer therapies, especially in <i>BRAF</i>-mutated and <i>MET</i>-addicted papillary thyroid carcinomas. SIGNIFICANCE: These results highlight the oncogenic role of lncRNA <i>COMET</i> in thyroid and indicate it as a potential new target to overcome vemurafenib resistance in <i>BRAF</i>-mutated and MET-addicted carcinomas.