<i>EIF1AX</i> and <i>NRAS</i> 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 <i>EIF1AX</i> and in <i>NF1, USP9X, KRAS, BRAF</i>, and <i>NRAS</i> RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in <i>NRAS</i> and <i>EIF1AX</i> Missense <i>EIF1AX</i> 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 <i>NRAS</i> and <i>EIF1AX</i> proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. <i>Cancer Res; 77(16); 4268-78. ©2017 AACR</i>.