EIF1AX and NRAS Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas

被引：64

作者：

Etemadmoghadam, Dariush ^{[1
,2
,3
]}

Azar, Walid J. ^{[1
]}

Lei, Ying ^{[4
,5
,6
]}

Moujaber, Tania ^{[4
,5
,6
,7
]}

Garsed, Dale W. ^{[1
,2
]}

Kennedy, Catherine J. ^{[4
,5
]}

Fereday, Sian ^{[1
]}

Mitchell, Chris ^{[1
]}

Chiew, Yoke-Eng ^{[4
,5
]}

Hendley, Joy ^{[1
]}

Sharma, Raghwa ^{[6
,8
,9
]}

Harnett, Paul R. ^{[4
,6
,7
]}

Li, Jason ^{[1
]}

Christie, Elizabeth L. ^{[1
]}

Patch, Ann-Marie ^{[10
]}

George, Joshy ^{[11
]}

Au-Yeung, George ^{[1
]}

Arnau, Gisela Mir ^{[1
]}

Holloway, Timothy P. ^{[1
]}

Semple, Timothy ^{[1
]}

Pearson, John V. ^{[10
]}

Waddell, Nicola ^{[10
]}

Grimmond, Sean M. ^{[12
]}

Kobel, Martin ^{[13
]}

Rizos, Helen ^{[14
]}

Lomakin, Ivan B. ^{[15
]}

Bowtell, David D. L. ^{[1
,2
,3
,16
,17
]}

deFazio, Anna ^{[4
,5
,6
]}

机构：

[1] Peter MacCallum Canc Ctr, 305 Grattan St, Melbourne, Vic 3000, Australia

[2] Univ Melbourne, Sir Peter MacCallum Canc Ctr, Dept Oncol, Melbourne, Vic, Australia

[3] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia

[4] Westmead Inst Med Res, Ctr Canc Res, Sydney, NSW, Australia

[5] Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia

[6] Univ Sydney, Sydney, NSW, Australia

[7] Westmead Hosp, Crown Princess Mary Canc Care Ctr, Sydney, NSW, Australia

[8] Pathol West ICPMR, Westmead, NSW, Australia

[9] Univ Western Sydney, Westmead Hosp, Westmead, NSW, Australia

[10] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[11] Jackson Lab Genom Med, Farmington, CT USA

[12] Univ Melbourne, Ctr Canc Res, Parkville, Vic, Australia

[13] Univ Calgary, Foothill Med Ctr, Dept Pathol & Lab Med, Calgary, AB, Canada

[14] Macquarie Univ, Dept Biomed Sci, Sydney, NSW, Australia

[15] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA

[16] Univ Melbourne, Dept Biochem & Mol Biol, Melbourne, Vic, Australia

[17] Garvan Inst Med Res, Kinghorn Canc Ctr, Sydney, NSW, Australia

来源：

CANCER RESEARCH | 2017年 / 77卷 / 16期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

START CODON SELECTION; TRANSLATION INITIATION COMPLEX; MESSENGER-RNAS; CANCER; RAS; MELANOMA; RIBOSOME; DISEASE; TUMORS; WOMEN;

D O I：

10.1158/0008-5472.CAN-16-2224

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. (C) 2017 AACR.

引用

页码：4268 / 4278

页数：11

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