title: 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.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Stark
authors.forename: Susan L
authors.initials: SL
authors.lastname: Woods
authors.forename: Michael G
authors.initials: MG
authors.lastname: Gartside
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Bonazzi
authors.forename: Ken
authors.initials: K
authors.lastname: Dutton-Regester
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Aoude
authors.forename: Donald
authors.initials: D
authors.lastname: Chow
authors.forename: Chris
authors.initials: C
authors.lastname: Sereduk
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Niemi
authors.forename: Nanyun
authors.initials: N
authors.lastname: Tang
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Ellis
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Reid
authors.forename: Victoria
authors.initials: V
authors.lastname: Zismann
authors.forename: Sonika
authors.initials: S
authors.lastname: Tyagi
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Irene
authors.initials: I
authors.lastname: Newsham
authors.forename: YuanQing
authors.initials: Y
authors.lastname: Wu
authors.forename: Jane M
authors.initials: JM
authors.lastname: Palmer
authors.forename: Thomas
authors.initials: T
authors.lastname: Pollak
authors.forename: David
authors.initials: D
authors.lastname: Youngkin
authors.forename: Bradford R
authors.initials: BR
authors.lastname: Brooks
authors.forename: Catherine
authors.initials: C
authors.lastname: Lanagan
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Schmidt
authors.forename: Bostjan
authors.initials: B
authors.lastname: Kobe
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: MacKeigan
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yin
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Trent
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D059472:Exome; D006801:Humans; D019656:Loss of Heterozygosity; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D008969:Molecular Sequence Data; D009154:Mutation; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003606:Dacarbazine; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; C433243:MAP3K9 protein, human; D000077204:Temozolomide