Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

被引：331

作者：

Nikolaev, Sergey I. ^{[1
]}

Rimoldi, Donata ^{[2
]}

Iseli, Christian ^{[2
,3
]}

Valsesia, Armand ^{[2
,4
]}

Robyr, Daniel ^{[1
]}

Gehrig, Corinne ^{[1
]}

Harshman, Keith ^{[5
]}

Guipponi, Michel ^{[1
]}

Bukach, Olesya ^{[6
]}

Zoete, Vincent ^{[3
]}

Michielin, Olivier ^{[2
,3
,7
]}

Muehlethaler, Katja ^{[2
]}

Speiser, Daniel ^{[2
]}

Beckmann, Jacques S. ^{[4
,8
]}

Xenarios, Ioannis ^{[3
]}

Halazonetis, Thanos D. ^{[9
]}

Jongeneel, C. Victor ^{[2
,3
,10
,11
]}

Stevenson, Brian J. ^{[2
,3
]}

Antonarakis, Stylianos E. ^{[1
,12
]}

机构：

[1] Univ Geneva, Dept Genet Med & Dev, Geneva, Switzerland

[2] Univ Lausanne, Ludwig Inst Canc Res, Lausanne, Switzerland

[3] Swiss Inst Bioinformat, Lausanne, Switzerland

[4] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland

[5] Ctr Integrat Gen, Lausanne Genom Technol Facil, Lausanne, Switzerland

[6] Univ Geneva, Dept Micorbiol & Mol Med, Geneva, Switzerland

[7] CHU Vaudois, Multidisciplinary Oncol Ctr, Lausanne, Switzerland

[8] CHU Vaudois, Serv Med Genet, Lausanne, Switzerland

[9] Univ Geneva, Dept Mol Biol, CH-1211 Geneva, Switzerland

[10] Univ Illinois, Natl Ctr Supercomp Applicat, Urbana, IL 61801 USA

[11] Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA

[12] Inst Genet & Genom Geneva iGE3, Geneva, Switzerland

来源：

NATURE GENETICS | 2012年 / 44卷 / 02期

基金：

瑞士国家科学基金会; 欧洲研究理事会;

关键词：

MALIGNANT-MELANOMA; GERMLINE MUTATIONS; MAPK PATHWAY; HUMAN BREAST; GENE; GENOME; BRAF; METASTASIS; MECHANISMS; BYPASS;

D O I：

10.1038/ng.1026

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：133 / 139

页数：7

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