GRCh38 · COSMIC v92


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Co-occurring Mutations of Tumor Suppressor Genes, LATS2 and NF2, in Malignant Pleural Mesothelioma.
Paper ID
Tranchant R, Quetel L, Tallet A, Meiller C, Renier A, de Koning L, de Reynies A, Le Pimpec-Barthes F, Zucman-Rossi J, Jaurand MC and Jean D
Génomique Fonctionnelle des Tumeurs Solides, INSERM, UMR-1162, Equipe labellisée Ligue Contre le Cancer, Paris, France.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017;23(12):3191-3202
ISSN: 1078-0432
PMID: 28003305 (view at PubMed or Europe PMC)
<b>Purpose:</b> To better define malignant pleural mesothelioma (MPM) heterogeneity and identify molecular subtypes of MPM, we focus on the tumor suppressor gene <i>LATS2</i>, a member of the Hippo signaling pathway, which plays a key role in mesothelial carcinogenesis.<b>Experimental Design:</b> Sixty-one MPM primary cultures established in our laboratory were screened for mutations in <i>LATS2</i> Gene inactivation was modeled using siRNAs. Gene and protein expressions were analyzed by quantitative RT-PCR, Western blot analysis, and reverse phase protein array. Cell proliferation, viability, apoptosis, mobility, and invasion were determined after siRNA knockdown or YAP (verteporfin), mTOR (rapamycin), and mTOR/PI3K/AKT (PF-04691502) inhibitor treatment.<b>Results:</b> The <i>LATS2</i> gene was altered in 11% of MPM by point mutations and large exon deletions. Genetic data coupled with transcriptomic data allowed the identification of a new MPM molecular subgroup, C2<sup>LN</sup>, characterized by a co-occurring mutation in the <i>LATS2</i> and <i>NF2</i> genes in the same MPM. MPM patients of this subgroup presented a poor prognosis. Coinactivation of <i>LATS2</i> and <i>NF2</i> leads to loss of cell contact inhibition between MPM cells. Hippo signaling pathway activity, mTOR expression, and phosphorylation were altered in the C2<sup>LN</sup> MPM subgroup. MPMs of this new subgroup show higher sensitivity to PF-04691502 inhibitor. The <i>MOK</i> gene was identified as a potential biomarker of the C2<sup>LN</sup> MPM subgroup and PF-04691502 sensitivity.<b>Conclusions:</b> We identified a new MPM molecular subgroup that shares common genetic and transcriptomic characteristics. Our results made it possible to highlight a greater sensitivity to an anticancer compound for this MPM subgroup and to identify a specific potential biomarker. <i>Clin Cancer Res; 23(12); 3191-202. ©2016 AACR</i>.
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