PIK3CA exon 20 mutations are associated with poor prognosis in breast cancer patients

Abstract

OBJECTIVES:The phosphatidylinositol 3-kinase/AKT axis is an important cell-signaling pathway that mediates cell proliferation and survival, two biological processes that regulate malignant cell growth. The phosphatidylinositol 3-kinase CA gene encodes the p110α subunit of the phosphatidylinositol 3-kinase protein. There are phosphatidylinositol 3-kinase CA mutations in several types of human tumors, and they are frequently observed in breast cancer. However, these mutations have not been investigated in Brazilian breast cancer patients.METHODS:PCR-SSCP and direct DNA sequencing were performed to identify phosphatidylinositol 3-kinaseCA exon 9 and exon 20 mutations in 86 patients with sporadic breast cancer. The relationships between PIK3CA mutations and patient clinicopathological characteristics and survival were analyzed. The presence of the TP53 mutation was also examined.RESULTS:Twenty-three (27%) of the 86 primary breast tumors contained PIK3CA mutations. In exons 9 and 20, we identified the hotspot mutations E542K, E545K, and H1047R, and we identified two new missense mutations (I1022V and L1028S) and one nonsense (R992X) mutation. Phosphatidylinositol 3-kinase CA exon 20 mutations were associated with poor overall survival and TP53 gene mutations.CONCLUSIONS:Phosphatidylinositol 3-kinase CA mutations are common in tumors in Brazilian breast cancer patients, and phosphatidylinositol 3-kinase CA and TP53 mutations are not mutually exclusive. Phosphatidylinositol 3-kinase CA exon 20 mutations are associated with poor survival, and they may be useful biomarkers for identifying breast cancer patients with aggressive tumors and for predicting the response to treatment with PI3K pathway inhibitors.

Pathway based identification of rare mutation effect in cancer

“…TP53 and PIK3CA are not mutually exclusive at the observation of TCGA breast cancer data, which is concordant to the previous report [11]. Heatmap visualization of unsupervised clustering of pathway level characteristics shows distinguishing subgroup pattern between "TP53 mutated and PIK3CA non-mutated samples enriched" subgroup (D, E and F) and "TP53 non-mutated and PIK3CA mutated samples enriched" subgroup (A, B and C).…”

Somatic mutations in breast and serous ovarian cancer young patients: a systematic review and meta-analysis

“…In these studies, however, a cut point was set at a higher age, 50-55 years or menopause. [62][63][64] On the other hand, a trend towards association between PIK3CA somatic mutation in older patients was also already reported.…”

PI3K/Akt-mediated regulation of p53 in cancer

“…Not surprisingly, correlation studies between PI3K/Akt mutations and p53 mutations have also suggested conflicting patient outcome. Furthermore, PIK3CA mutations (exon 20) were recently reported to have a positive correlation with p53 mut in breast cancer [74], in direct contrast with the data presented by Boyault et al [72]. At the same time, the presence of high p53 expression (clinically interpreted as p53 mut ) in HER2 + breast tumours is associated with better outcome following trastuzumab treatment [73].…”