Oncotarget

Research Papers:

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

Xiang Li, Ruishan Zhang, Zhuangkai Liu, Shuang Li and Hong Xu _

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Oncotarget. 2017; 8:20252-20265. https://doi.org/10.18632/oncotarget.15690

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Abstract

Xiang Li1, Ruishan Zhang1, Zhuangkai Liu1, Shuang Li1, Hong Xu1

1Department of Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Dadong District, Shenyang City, Liaoning Province, 110042, P.R.China

Correspondence to:

Hong Xu, email: [email protected]

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

Received: August 24, 2016     Accepted: January 04, 2017     Published: February 25, 2017

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.


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