High Frequency of PIK3R1 Alterations in Ovarian Cancers: Clinicopathological and Molecular Associations

Abstract

Background: The phosphoinositide 3-kinase (PI3K) pathway is activated in multiple cancers. However, the significance of PIK3R1 encoding the PI3K regulatory subunit, an inhibitor of the PI3K catalytic subunit encoded by PIK3CA, in ovarian cancer development is largely unknown.

Methods: Here, we investigated PIK3R1 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 PIK3R1 mRNA levels in ovarian carcinomas (95.8%). Tumors with PIK3R1 mutations mostly represented low-stage cancers of endometrioid and clear-cell type. Tumors with PIK3R1 deletion and underexpression shared similar phenotypes of high-grade carcinomas (p = 0.003 and p = 0.025, respectively). Allelic loss was also associated with advanced stages (p = 0.003) and high-grade serous histotypes (p = 0.004). The PIK3R1 copy number correlated with mRNA levels (p = 0.009). PIK3R1 mutations coexisted with PTEN mutations (p = 0.041), whereas PIK3R1 deletion and underexpression were linked to PIK3CA amplification (p = 0.038 and p = 0.033, respectively). Low PIK3R1 expression diminished the probability of a complete response (OR 0.07, p = 0.03) in patients treated with platinum-based regimens.

Conclusions: PIK3R1 alterations may contribute to the development of ovarian cancers with different malignant potential and molecular changes. The high frequency of PIK3R1 aberrations suggests their importance in PI3K pathway deregulation, and they may potentially serve as an alternative to PIK3CA markers for therapy with these pathway inhibitors.

Keywords: PI3K; PIK3CA; PIK3R1; gene copy number; gene expression; mutation; ovarian cancer; p85α.

Figure 1

PIK3R1 alterations in ovarian cancers: (A) the location of individual mutations within the PIK3R1 gene in ovarian cancers. (B) PIK3R1, PIK3CA, PTEN, KRAS, and TP53 mutations in endometrioid and clear-cell ovarian cancers. Mutated tumors (blue) are distinguished from tumors with no detectable mutation (white). The mutation frequency for individual genes is shown on the right. (C) PIK3R1 gene copy number plotted against PIK3R1 mRNA expression normalized to reference genes. The tumor (case 337) with the highest expression (equaling 1) was used as the calibrator. The line is shown to visualize trends in the expression change. (D) Prognostic significance of PIK3R1 expression. Patients with low PIK3R1 mRNA levels in ovarian tumors tended to have better disease-free survival (DFS) than patients with high expression (Kaplan–Meier curve).