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

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. Cancer Res; 77(16); 4268-78. (c)2017 AACR.

Type Journal
ISBN 1538-7445 (Electronic) 0008-5472 (Linking)
Authors Etemadmoghadam, D.; Azar, W. J.; Lei, Y.; Moujaber, T.; Garsed, D. W.; Kennedy, C. J.; Fereday, S.; Mitchell, C.; Chiew, Y. E.; Hendley, J.; Sharma, R.; Harnett, P. R.; Li, J.; Christie, E. L.; Patch, A. M.; George, J.; Au-Yeung, G.; Mir Arnau, G.; Holloway, T. P.; Semple, T.; Pearson, J. V.; Waddell, N.; Grimmond, S. M.; Kobel, M.; Rizos, H.; Lomakin, I. B.; Bowtell, D. D. L.; deFazio, A.; Australian Ovarian Cancer Study, Group
Garvan Authors Prof David Bowtell
Publisher Name CANCER RESEARCH
Published Date 2017-08-15 00:00:00
Published Volume 77
Published Issue 16
Published Pages 4268-4278
URL https://www.ncbi.nlm.nih.gov/pubmed/28646021
Status Published in-print