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Stark MS, Woods SL, Gartside MG et al.Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nat Genet 44:165-169

Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Nature Genetics (Impact Factor: 29.65). 12/2011; 44(2):165-9. DOI: 10.1038/ng.1041
Source: PubMed

ABSTRACT We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.

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    • "We also observed three recurrent alterations at S278F, E371K, and E1175K as well as five nonsense mutations. Recently, another group recently published a whole-exome screen of eight melanoma samples and found two additional somatic mutations in GRIN2A, suggesting that genetic alteration of this gene is important (Stark et al., 2011). Furthermore, seven somatic mutations found in our screen have been discovered by others as well as some listed in the COSMIC database (D252N, S278F, W343X, G449E, M653I, R920K, S929F, and E1073K; Berger et al., 2012; Hodis et al., 2012) (http://cancer.sanger. "
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    • "Recently, an exome sequencing analysis of melanoma cell lines identified gene-wide nonsynonymous somatic mutations of MAP3K5 in 8 of 85 melanomas (Stark et al., 2012). However , in contrast to this study, the MAP3K5 mutations analyzed had little to no effect on downstream activation or suppression of c-Jun N-terminal kinase or p38, nor did we observe a negative effect on the MEK/MAPK pathway for the MAP3K5 R256C mutation. "
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    • "Mutations in the BRAF and NRAS oncogenes are the most important drivers of melanoma development, activating the mitogen-activated protein kinase (MAPK) pathway that mediates proliferative signals. This signaling pathway is additionally disrupted in melanoma by recurrent mutations in MAP2K1, MAP2K2, MAP3K5, and MAP3K9 (Nikolaev et al., 2012; Stark et al., 2012). "
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