Whole-exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells
| Autor: | Mariusz L. Hartman, Malgorzata Czyz, Malgorzata Sztiller-Sikorska |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Senescence Cancer Research Apoptosis Biology 03 medical and health sciences 0302 clinical medicine CDKN2A Exome Sequencing Biomarkers Tumor Tumor Cells Cultured medicine Humans Phosphorylation Vemurafenib Melanoma Protein Kinase Inhibitors Molecular Biology Cellular Senescence PI3K/AKT/mTOR pathway Cell Proliferation YAP1 Trametinib Cell Cycle medicine.disease Phenotype 030104 developmental biology 030220 oncology & carcinogenesis Mutation Cancer research medicine.drug |
| Zdroj: | Molecular Carcinogenesis. 58:588-602 |
| ISSN: | 0899-1987 |
| Popis: | We have extensively studied the phenotypic heterogeneity of patient-derived melanoma cells. Here, whole-exome sequencing revealed novel variants of genes associated with the MAPK, NOTCH, Hippo, cell-cycle, senescence, and ubiquitin-dependent pathways, which could contribute to the observed phenotypic diversity between cell lines. Focusing on mutations in the MAPK pathway-associated genes, we found BRAF (BRAFV600E ) and RAS subtypes, including NRASQ61R and the rare HRASQ61R variant, and additional alterations potentially leading to different ERK1/2 activity. Both RASQ61R cell lines harbored a MEK1P124S variant and exerted a low level of phospho-MEK1/2. Activity of the MAPK pathway was further attenuated in NRASQ61R /MEKP124S cells by trametinib, and this effect was also shown in HRASQ61R /MEKP124S melanoma cells. The observed variability in doubling time might be a consequence of diverse MAPK and PI3K/AKT pathway activities, but not exclusively, as a senescence program was also executed to different extent in distinct melanoma cell lines. Low percentages of senescent cells might result from mutations in CDKN2A, E2F3, and EZH2, and a high c-MYC expression. Vemurafenib and trametinib induced senescence concomitantly with c-MYC downregulation and irrespectively of CDKN2A mutation, but the EZH2S412C variant might limit senescence induction. Damaging alterations in Hippo pathway-associated genes were accompanied with variability in the phosphorylation level of YAP1/TAZ and CTGF expression. Our study also suggests opposite activity of NOTCH2F1209V and NOTCH2N2002S variants. Additionally, we found a novel FBXW7V418M variant that retained its function in melanoma cells. The obtained molecular data might be further exploited in genotype-phenotype relationship studies and in identifying novel biomarkers and therapies for melanomas. |
| Databáze: | OpenAIRE |
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