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

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

doi:10.1038/ng.1041

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

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

School of Health Professions

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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.

Original language	English (US)
Pages (from-to)	165-169
Number of pages	5
Journal	Nature Genetics
Volume	44
Issue number	2
DOIs	https://doi.org/10.1038/ng.1041
State	Published - Feb 2012

ASJC Scopus subject areas

Genetics

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Stark, M. S., Woods, S. L., Gartside, M. G., Bonazzi, V. F., Dutton-Regester, K., Aoude, L. G., Chow, D., Sereduk, C., Niemi, N. M., Tang, N., Ellis, J. J., Reid, J., Zismann, V., Tyagi, S., Muzny, D., Newsham, I., Wu, Y., Palmer, J. M., Pollak, T., ... Hayward, N. K. (2012). Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nature Genetics, 44(2), 165-169. https://doi.org/10.1038/ng.1041

Stark, MS, Woods, SL, Gartside, MG, Bonazzi, VF, Dutton-Regester, K, Aoude, LG, Chow, D, Sereduk, C, Niemi, NM, Tang, N, Ellis, JJ, Reid, J, Zismann, V, Tyagi, S, Muzny, D, Newsham, I, Wu, Y, Palmer, JM, Pollak, T, Youngkin, D, Brooks, BR, Lanagan, C, Schmidt, CW, Kobe, B, MacKeigan, JP, Yin, H, Brown, KM, Gibbs, R, Trent, J & Hayward, NK 2012, 'Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing', Nature Genetics, vol. 44, no. 2, pp. 165-169. https://doi.org/10.1038/ng.1041

@article{18237abe8f7b4e56b0954c1a464647fb,

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.",

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

note = "Funding Information: The authors would like to acknowledge M. Aziz for data processing, M. Kassner for technical support and J.-C. Deza for graphics support. This work was funded through grants from the National Health and Medical Research Council of Australia, the Australian Centre for Vaccine Development, the US National Cancer Institute (5U01CA129447 to J.T.), the US National Cancer Institute, Division of Cancer Epidemiology and Genetics (to K.M.B.), and a charitable donation by Francis Najafi (to K.M.B. and J.T.).",

year = "2012",

month = feb,

doi = "10.1038/ng.1041",

language = "English (US)",

volume = "44",

pages = "165--169",

journal = "Nature Genetics",

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T1 - Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing

AU - Stark, Mitchell S.

AU - Woods, Susan L.

AU - Gartside, Michael G.

AU - Bonazzi, Vanessa F.

AU - Dutton-Regester, Ken

AU - Aoude, Lauren G.

AU - Chow, Donald

AU - Sereduk, Chris

AU - Niemi, Natalie M.

AU - Tang, Nanyun

AU - Ellis, Jonathan J.

AU - Reid, Jeffrey

AU - Zismann, Victoria

AU - Tyagi, Sonika

AU - Muzny, Donna

AU - Newsham, Irene

AU - Wu, Yuanqing

AU - Palmer, Jane M.

AU - Pollak, Thomas

AU - Youngkin, David

AU - Brooks, Bradford R.

AU - Lanagan, Catherine

AU - Schmidt, Christopher W.

AU - Kobe, Bostjan

AU - MacKeigan, Jeffrey P.

AU - Yin, Hongwei

AU - Brown, Kevin M.

AU - Gibbs, Richard

AU - Trent, Jeffrey

AU - Hayward, Nicholas K.

N1 - Funding Information: The authors would like to acknowledge M. Aziz for data processing, M. Kassner for technical support and J.-C. Deza for graphics support. This work was funded through grants from the National Health and Medical Research Council of Australia, the Australian Centre for Vaccine Development, the US National Cancer Institute (5U01CA129447 to J.T.), the US National Cancer Institute, Division of Cancer Epidemiology and Genetics (to K.M.B.), and a charitable donation by Francis Najafi (to K.M.B. and J.T.).

PY - 2012/2

Y1 - 2012/2

N2 - 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.

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

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