EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas

Dariush Etemadmoghadam, Walid J. Azar, Ying Lei, Tania Moujaber, Dale W. Garsed, Catherine J. Kennedy, Sian Fereday, Chris Mitchell, Yoke Eng Chiew, Joy Hendley, Raghwa Sharma, Paul R. Harnett, Jason Li, Elizabeth L. Christie, Ann Marie Patch, Joshy George, George Au-Yeung, Gisela Mir Arnau, Timothy P. Holloway, Timothy Semple & 8 others John V. Pearson, Nicola Waddell, Sean M. Grimmond, Martin Köbel, Helen Rizos, Ivan B. Lomakin, David D.L. Bowtell*, Anna deFazio

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4268-4278
Number of pages11
JournalCancer Research
Volume77
Issue number16
DOIs
Publication statusPublished - 15 Aug 2017

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