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. ©2017 AACR.
Highlights
Low-grade serous ovarian carcinomas (LGSC) differ from high-grade serous ovarian cancer (HGSC) by having RAS– MAPK pathway mutations [1], few DNA copy-number changes, a lower rate of somatic mutation, and wild-type TP53 [2]
Survival analysis showed a trend toward improved progression-free and overall survival in LGSC patients debulked to no macroscopic residual disease
Survival was equivalent in patients with grade 1 (LGSC) and grade 3 (HGSC) tumors, if macroscopic residual disease remained after debulking surgery
Summary
Low-grade serous ovarian carcinomas (LGSC) differ from high-grade serous ovarian cancer (HGSC) by having RAS– MAPK pathway mutations [1], few DNA copy-number changes, a lower rate of somatic mutation, and wild-type TP53 [2]. Response to the BRAF inhibitor vemurafenib has MacCallum Cancer Centre Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
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