Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

Sergey I. Nikolaev; Donata Rimoldi; Christian Iseli; Armand Valsesia; Daniel Robyr; Corinne Gehrig; Keith Harshman; Michel Guipponi; Olesya Bukach; Vincent Zoete; Olivier Michielin; Katja Muehlethaler; Daniel Speiser; Jacques S. Beckmann; Ioannis Xenarios; Thanos D. Halazonetis; C. Victor Jongeneel; Brian J. Stevenson; Stylianos E. Antonarakis

doi:10.1038/ng.1026

Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

Sergey I. Nikolaev, Donata Rimoldi, Christian Iseli, Armand Valsesia, Daniel Robyr, Corinne Gehrig, Keith Harshman, Michel Guipponi, Olesya Bukach, Vincent Zoete, Olivier Michielin, Katja Muehlethaler, Daniel Speiser, Jacques S. Beckmann, Ioannis Xenarios, Thanos D. Halazonetis, C. Victor Jongeneel, Brian J. Stevenson, Stylianos E. Antonarakis

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

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Résumé

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

langue originale	Anglais
Pages (de - à)	133-139
Nombre de pages	7
journal	Nature Genetics
Volume	44
Numéro de publication	2
Les DOIs	https://doi.org/10.1038/ng.1026
état	Publié - 1 janv. 2012
Modification externe	Oui

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10.1038/ng.1026

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Nikolaev, S. I., Rimoldi, D., Iseli, C., Valsesia, A., Robyr, D., Gehrig, C., Harshman, K., Guipponi, M., Bukach, O., Zoete, V., Michielin, O., Muehlethaler, K., Speiser, D., Beckmann, J. S., Xenarios, I., Halazonetis, T. D., Jongeneel, C. V., Stevenson, B. J., & Antonarakis, S. E. (2012). Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nature Genetics, 44(2), 133-139. https://doi.org/10.1038/ng.1026

@article{18f761f0e20747a08ee27a121b4e38a4,

title = "Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma",

abstract = "We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.",

author = "Nikolaev, {Sergey I.} and Donata Rimoldi and Christian Iseli and Armand Valsesia and Daniel Robyr and Corinne Gehrig and Keith Harshman and Michel Guipponi and Olesya Bukach and Vincent Zoete and Olivier Michielin and Katja Muehlethaler and Daniel Speiser and Beckmann, {Jacques S.} and Ioannis Xenarios and Halazonetis, {Thanos D.} and Jongeneel, {C. Victor} and Stevenson, {Brian J.} and Antonarakis, {Stylianos E.}",

note = "Funding Information: We thank F. Sch{\"u}tz and P. Bady for statistical discussions, P. Descombes for high-throughput sequencing, D. Martinet for aCGH data and C. Rivolta for valuable comments on the manuscript. We thank A. Simpson and R. Strausberg for their constant support. Part of the computation was performed on the cluster at the Vital-IT computing center. This work was supported by the Ludwig Institute for Cancer Research (C.I. and S.E.A.), the Hilton-Ludwig Cancer Metastasis Initiative, funded by the Conrad N. Hilton Foundation (D.R.), the Swiss National Science Foundation (SNF) National Centres of Competence in Research (NCCR) Frontiers in Genetics (S.E.A.) and the European Research Council (ERC; S.E.A.).",

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doi = "10.1038/ng.1026",

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Nikolaev, SI, Rimoldi, D, Iseli, C, Valsesia, A, Robyr, D, Gehrig, C, Harshman, K, Guipponi, M, Bukach, O, Zoete, V, Michielin, O, Muehlethaler, K, Speiser, D, Beckmann, JS, Xenarios, I, Halazonetis, TD, Jongeneel, CV, Stevenson, BJ & Antonarakis, SE 2012, 'Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma', Nature Genetics, VOL. 44, Numéro 2, p. 133-139. https://doi.org/10.1038/ng.1026

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T1 - Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

AU - Nikolaev, Sergey I.

AU - Rimoldi, Donata

AU - Iseli, Christian

AU - Valsesia, Armand

AU - Robyr, Daniel

AU - Gehrig, Corinne

AU - Harshman, Keith

AU - Guipponi, Michel

AU - Bukach, Olesya

AU - Zoete, Vincent

AU - Michielin, Olivier

AU - Muehlethaler, Katja

AU - Speiser, Daniel

AU - Beckmann, Jacques S.

AU - Xenarios, Ioannis

AU - Halazonetis, Thanos D.

AU - Jongeneel, C. Victor

AU - Stevenson, Brian J.

AU - Antonarakis, Stylianos E.

N1 - Funding Information: We thank F. Schütz and P. Bady for statistical discussions, P. Descombes for high-throughput sequencing, D. Martinet for aCGH data and C. Rivolta for valuable comments on the manuscript. We thank A. Simpson and R. Strausberg for their constant support. Part of the computation was performed on the cluster at the Vital-IT computing center. This work was supported by the Ludwig Institute for Cancer Research (C.I. and S.E.A.), the Hilton-Ludwig Cancer Metastasis Initiative, funded by the Conrad N. Hilton Foundation (D.R.), the Swiss National Science Foundation (SNF) National Centres of Competence in Research (NCCR) Frontiers in Genetics (S.E.A.) and the European Research Council (ERC; S.E.A.).

PY - 2012/1/1

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N2 - We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

AB - We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

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