EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas
A partir d'échantillons tumoraux prélevés sur des patientes atteintes d'un carcinome séreux de l'ovaire de bas grade, puis menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels des protéines exprimées par deux gènes mutés, EIF1AX et NRAS, coopèrent pour favoriser la croissance d'une tumeur ovarienne
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. Co-expression 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 Research 2017