Enhanced GAB2 expression is associated with improved survival in high-grade serous ovarian cancer and sensitivity to PI3K inhibition.

abstract

Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterised high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36 and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas data sets were also used to assess the correlation between gene expression, patient survival and tumour classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P=0.03 and 0.02), while high BMP8B and ATP13A4 were associated with improved progression-free survival (P=0.004 and P=0.02). GAB2 over expression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual phosphoinositide-3-kinase (PI3K)/mTOR inhibitor, PF-04691502, and could be used as a genomic marker for identifying patients that will respond to treatments inhibiting PI3K signalling.