High Frequency of Alterations in Ovarian Cancers: Clinicopathological and Molecular Associations

Background: The phosphoinositide 3-kinase (PI3K) pathway is activated in multiple cancers. However, the significance of encoding the PI3K regulatory subunit, an inhibitor of the PI3K catalytic subunit encoded by , in ovarian cancer development is largely unknown.

Methods: Here, we investigated genomic alterations and gene expression by direct sequencing and qPCR methods in 197 ovarian cancers. The results were correlated with clinicopathological and molecular variables and patient outcomes.

Results: In addition to mutations (3.5%) and allelic losses (28.4%), we observed a very high frequency of decreased mRNA levels in ovarian carcinomas (95.8%). Tumors with mutations mostly represented low-stage cancers of endometrioid and clear-cell type. Tumors with deletion and underexpression shared similar phenotypes of high-grade carcinomas ( = 0.003 and = 0.025, respectively). Allelic loss was also associated with advanced stages ( = 0.003) and high-grade serous histotypes ( = 0.004). The copy number correlated with mRNA levels ( = 0.009). mutations coexisted with mutations ( = 0.041), whereas deletion and underexpression were linked to amplification ( = 0.038 and = 0.033, respectively). Low expression diminished the probability of a complete response (OR 0.07, = 0.03) in patients treated with platinum-based regimens.

Conclusions: alterations may contribute to the development of ovarian cancers with different malignant potential and molecular changes. The high frequency of aberrations suggests their importance in PI3K pathway deregulation, and they may potentially serve as an alternative to markers for therapy with these pathway inhibitors.