Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

被引：319

作者：

Krauthammer, Michael ^{[1
,2
]}

Kong, Yong ^{[3
]}

Bacchiocchi, Antonella ^{[4
]}

Evans, Perry ^{[1
]}

Pornputtapong, Natapol ^{[2
]}

Wu, Cen ^{[5
]}

McCusker, James P. ^{[2
]}

Ma, Shuangge ^{[5
]}

Cheng, Elaine ^{[4
]}

Straub, Robert ^{[4
]}

Serin, Merdan ^{[4
]}

Bosenberg, Marcus ^{[2
,4
]}

Ariyan, Stephan ^{[6
]}

Narayan, Deepak ^{[6
]}

Sznol, Mario ^{[7
]}

Kluger, Harriet M. ^{[7
]}

Mane, Shrikant ^{[8
,9
]}

Schlessinger, Joseph ^{[10
]}

Lifton, Richard P. ^{[9
,11
]}

Halaban, Ruth ^{[4
]}

机构：

[1] Yale Univ, Sch Med, Program Computat Biol & Bioinformat, New Haven, CT USA

[2] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA

[3] Yale Univ, Sch Med, Mol Biophys & Biochem, New Haven, CT USA

[4] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA

[5] Yale Univ, Sch Med, Sch Publ Hlth, New Haven, CT USA

[6] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA

[7] Yale Univ, Sch Med, Ctr Comprehens Canc, Sect Med Oncol, New Haven, CT 06510 USA

[8] Yale Univ, Sch Med, Yale Ctr Genome Anal, New Haven, CT USA

[9] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[10] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA

[11] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 09期

基金：

美国国家卫生研究院;

关键词：

TERT PROMOTER MUTATIONS; AU-LAIT SPOTS; NOONAN-SYNDROME; CUTANEOUS MELANOMA; NEUROFIBROMATOSIS TYPE-1; SOMATIC MUTATIONS; TUMOR-SUPPRESSOR; PTPN11; MUTATIONS; LEGIUS SYNDROME; RAF INHIBITION;

D O I：

10.1038/ng.3361

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis.

引用

页码：996 / +

页数：9

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