The genetic variants in the PTEN/PI3K/AKT pathway predict susceptibility and CE(A)F chemotherapy response to breast cancer and clinical outcomes

Abstract

The PI3K/PTEN/AKT pathway play a critical role in balancing cell growth and death. Epidemiologic studies suggested that mutations of the PI3K/PTEN/AKT pathway genes are associated with cancer risk, yet no data are available for PTEN rs701848, PIK3CA rs2699887, and AKT1 rs2494752 polymorphism and breast cancer(BC) risk. A case-control study was performed in 920 BC patients and 908 healthy controls using the TaqMan assay method. Overall, individuals with PTEN rs701848 TC, CC and TC/CC genotypes showed significant increased BC risk (P=0.043, P=0.002, P=0.008, respectively), and the C allele carriers had a 1.224-fold significantly increased risk of developing BC (P= 0.003). Moreover, a higher frequency of AKT rs2494752 AG genotype was observed among cases (P=0.045). Individuals harboring rs2494752 AG/AA genotype had a vital increased susceptibility to BC in the dominant model (P=0.039). More importantly, AKT1 rs2494752 GG genotype showed significantly rates of response to NCT chemotherapy (P=0.048). Furthermore, AKT1 rs2494752 AG genotype carriers showed significantly shorter DFS time, and GG genotype as the independent prognostic factor (DFS: adjusted HR=1.523, 95% CI=1.012-2.293, P=0.044; OS: adjusted HR=2.321, 95% CI=1.281-4.204, P=0.005). Moreover, MDR analysis consistently revealed that the combination of 3 selected SNPs and 7 known risk factors represented the best model to predicting BC prognosis. The luciferase assay showed that the G allele of rs2494752 significantly increased AKT1 promoter activity. These results suggest that PTEN rs701848 and AKT1 rs2494752 polymorphisms might be a candidate pharmacogenomic factor to assess the susceptibility of BC and response and prognosis prediction for interindividualized CE(A)F chemotherapy in BC patients.

Keywords: PTEN/PI3K/AKT pathway; breast cancer; genetic polymorphisms; prognosis; susceptibility.

Figure 1. Hstogram and box plots illustrating the frequency distribution of AKT1 rs2494752 polymorphism and stratified clinicopathological features

Frequency distribution of AKT1 rs2494752 genotypes classified by age of onset (<52 years, ≥52 years) A. and Lymph node metastasis (Node-negative, Node-positive) B.

Figure 2. The relationship between the AKT1 rs2494752 polymorphism and BC prognosis according to Kaplan-Meier analysis

PIK3CA rs2699887 GA/GG genotype had longer DFS A. and OS B. in BC patients with CE(A)F regimen chemotherapy. AKT1 rs2494752 AG genotype had shorter DFS C., but no correlation with OS D. in BC patients after CE(A)F regimen chemotherapy. AKT1 rs2494752 GG genotype had shorter DFS E. and OS F. in BC patients after CE(A)F regimen chemotherapy.

Figure 3. Effect of the rs2494752 polymorphism on the AKT1 promoter activity

Schematic representation of reporter plasmids containing the AKT1 rs2494752 A or G allele A., and the two constructs were transiently transfected into the 293T and MCF7 cells B. Data were measured as mean ± standard deviation (SD) from 3 separate experiments that were each performed in triplicate (*P<0.05).