Journal Article

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

Gartside, Michael G, Wu, YuanQing, Youngkin, David, Kobe, Bostjan, Niemi, Natalie M, Woods, Susan L, Brown, Kevin M, Trent, Jeffrey, Chow, Donald, Ellis, Jonathan J, Gibbs, Richard, Tyagi, Sonika, Tang, Nanyun, Zismann, Victoria, Pollak, Thomas, Lanagan, Catherine, Aoude, Lauren G, Stark, Mitchell S, Reid, Jeffrey, Schmidt, Christopher W, Palmer, Jane M, Muzny, Donna, Brooks, Bradford R, Bonazzi, Vanessa F, Dutton-Regester, Ken, Yin, Hongwei, MacKeigan, Jeffrey P, Hayward, Nicholas K, Sereduk, Chris, Newsham, Irene

2012

Overview

Nicholas Hayward and colleagues sequenced eight metastatic melanoma exomes and identified frequent somatic mutations in two MAP kinase family genes, MAP3K5 and MAP3K9 . Mutation in MAP3K9 may confer resistance to temozolomide, a common chemotherapeutic drug. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144/68 / 631/208/737 / 692/699/67/1813/1634 / Agriculture / Animal Genetics and Genomics / Antineoplastic Agents - pharmacology / Base Sequence / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer cells / Cancer Research / Cell Line, Tumor / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Dacarbazine - analogs & derivatives / Dacarbazine - pharmacology / Dermatology / Exome / Exome sequencing / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Human Genetics / Humans / Kinases / letter / Loss of Heterozygosity / MAP Kinase Kinase Kinase 5 - genetics / MAP Kinase Kinase Kinases - genetics / Medical sciences / Melanoma / Melanoma - drug therapy / Melanoma - genetics / Melanoma - secondary / Mitogen-activated protein kinases / Molecular and cellular biology / Molecular Sequence Data / Mutation / Proteins / Sequence Analysis, DNA / Sequence Homology, Nucleic Acid / Skin Neoplasms - drug therapy / Skin Neoplasms - genetics / Skin Neoplasms - pathology / Temozolomide / Tumor Cells, Cultured / Tumors of the skin and soft tissue. Premalignant lesions