Dataset Information

Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing.

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.

SUBMITTER: Stark MS

PROVIDER: S-EPMC3267896 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing.

Stark Mitchell S MS Woods Susan L SL Gartside Michael G MG Bonazzi Vanessa F VF Dutton-Regester Ken K Aoude Lauren G LG Chow Donald D Sereduk Chris C Niemi Natalie M NM Tang Nanyun N Ellis Jonathan J JJ Reid Jeffrey J Zismann Victoria V Tyagi Sonika S Muzny Donna D Newsham Irene I Wu YuanQing Y Palmer Jane M JM Pollak Thomas T Youngkin David D Brooks Bradford R BR Lanagan Catherine C Schmidt Christopher W CW Kobe Bostjan B MacKeigan Jeffrey P JP Yin Hongwei H Brown Kevin M KM Gibbs Richard R Trent Jeffrey J Hayward Nicholas K NK

Nature genetics 20111225 2

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 MA ...[more]

PMID: 22197930

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Project description:Clear cell renal cell carcinoma (ccRCC) is among the most aggressive histologic subtypes of kidney cancer, representing about 3% of all human cancers. Patients at stage IV have nearly 60% of mortality in 2-3 years after diagnosis. To date, most ccRCC studies have used DNA microarrays and targeted sequencing of a small set of well-established, commonly altered genes. An exception is the large multi-omics study of The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC), which identified new ccRCC genes based on whole exome-sequencing (WES) data, and molecular prognostic signatures based on transcriptomics, epigenetics and proteomics data. Applying WES to simultaneously interrogate virtually all exons in the human genome for somatic variation, here we analyzed the burden of coding somatic mutations in metastatic ccRCC primary tumors, and its association with patient mortality from cancer, in patients who received VEGF receptor-targeting drugs as the first-line therapy. To this end, we sequenced the exomes of ten tumor-normal pairs of ccRCC patient tissues from primary biopsies at >100× mean depth and called somatic coding variation. Mutation burden analysis prioritized 138 genes linked to patient mortality. A gene set enrichment analysis evidenced strong statistical support for the abundance of genes involved in the development of kidney cancer (p = 2.31 × 10-9) and carcinoma (p = 1.22 × 10-5), with 49 genes having direct links with kidney cancer according to the published records. Two of these genes, SIPA1L2 and EIF3A, demonstrated independent associations with mortality in TCGA-KIRC project data. Besides, three mutational signatures were found to be operative in the tumor exomes, one of which (COSMIC signature 12) has not been previously reported in ccRCC. Selection analysis yielded no detectable evidence of overall positive or negative selection, with the exome-wide number of nonsynonymous substitutions per synonymous site reflecting largely neutral tumor evolution. Despite the limited sample size, our results provide evidence for candidate genes where somatic mutation burden is tentatively associated with patient mortality in metastatic ccRCC, offering new potential pharmacological targets and a basis for further validation studies.

Dataset Information

Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing.

Publications

Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing.

Similar Datasets

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