Abstract
BackgroundThe present study focused on the prognostic roles of PIK3CA and PIK3R1 genes and additional PI3K pathway-associated genes in breast cancer.MethodsThe mutational and mRNA expression status of PIK3CA, PIK3R1 and AKT1, and expression status of other genes involved in the PI3K pathway (EGFR, PDK1, PTEN, AKT2, AKT3, GOLPH3, WEE1, P70S6K) were assessed in a series of 458 breast cancer samples.ResultsPIK3CA mutations were identified in 151 samples (33.0%) in exons 1, 2, 9 and 20. PIK3R1 mutations were found in 10 samples (2.2%) and underexpression in 283 samples (61.8%). AKT1 mutations were found in 15 samples (3.3%) and overexpression in 116 samples (25.3%). PIK3R1 underexpression tended to mutual exclusivity with PIK3CA mutations (p = 0.00097). PIK3CA mutations were associated with better metastasis-free survival and PIK3R1 underexpression was associated with poorer metastasis-free survival (p = 0.014 and p = 0.00028, respectively). By combining PIK3CA mutation and PIK3R1 expression status, four prognostic groups were identified with significantly different metastasis-free survival (p = 0.00046). On Cox multivariate regression analysis, the prognostic significance of PIK3R1 underexpression was confirmed in the total population (p = 0.0013) and in breast cancer subgroups.ConclusionsPIK3CA mutations and PIK3R1 underexpression show opposite effects on patient outcome and could become useful prognostic and predictive factors in breast cancer.
Highlights
The present study focused on the prognostic roles of Phosphatidylinositol 3-kinase (PIK3CA) and PIK3R1 genes and additional phosphatidylinositol 3-kinase (PI3K) pathway-associated genes in breast cancer
PIK3CA, PIK3R1 and AKT1 mutational analysis The present study extends our previously published data describing the positive effect of PIK3CA exon 9 and 20 mutations on breast cancer patient survival [12]
Breast cancer subgroup analysis demonstrated PIK3CA mutations with the lowest frequency (10/69; 14.5%) in Hormone receptors (HR)-/ERBB2- tumors and the highest frequency (118/290; 40.7%) in HR+/ERBB2- tumors, while an intermediate frequency of PIK3CA mutations was observed in HR-/ERBB2+ and HR+/ERBB2+ tumors (9/45; 20.0% and 14/54; 25.9%, respectively)
Summary
The present study focused on the prognostic roles of PIK3CA and PIK3R1 genes and additional PI3K pathway-associated genes in breast cancer. AKT regulates activation of the pathway downstream effectors, including mTOR and subsequently P70S6K as well as other targets such as GSK3, WEE1 or BAD. PI3K pathway deregulation is frequent in tumor cells and can be caused by multiple changes affecting different levels of the signaling cascade. These changes include gene amplifications, mutations and expression alterations. Various patterns of PI3K pathway changes have been identified in different cancer types. In breast cancer, such events commonly affect receptor tyrosine kinases, PTEN, PIK3CA and, to a lesser degree, AKT1. PIK3CA as well as AKT1 mutations have been described as early events in the breast cancer development process [3,4,5,6]
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