Li Xiang, Zhang Ruishan, Liu Zhuangkai, Li Shuang, Xu Hong
Department of Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Dadong District, Shenyang City, Liaoning Province, 110042, P.R.China.
Oncotarget. 2017 Mar 21;8(12):20252-20265. doi: 10.18632/oncotarget.15690.
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.
PI3K/PTEN/AKT信号通路在平衡细胞生长与死亡过程中发挥着关键作用。流行病学研究表明，PI3K/PTEN/AKT信号通路基因的突变与癌症风险相关，但关于PTEN基因rs701848、PIK3CA基因rs2699887以及AKT1基因rs2494752多态性与乳腺癌（BC）风险的相关数据尚无报道。本研究采用TaqMan检测法，对920例BC患者和908例健康对照者进行了病例对照研究。总体而言，PTEN基因rs701848的TC、CC以及TC/CC基因型个体的BC风险显著增加（分别为P = 0.043、P = 0.002、P = 0.008），且C等位基因携带者患BC的风险显著增加1.224倍（P = 0.003）。此外，病例组中AKT基因rs2494752的AG基因型频率更高（P = 0.045）。在显性模型中，携带rs2494752的AG/AA基因型个体对BC的易感性显著增加（P = 0.039）。更重要的是，AKT1基因rs2494752的GG基因型对新辅助化疗（NCT）的反应率显著不同（P = 0.048）。此外，AKT1基因rs2494752的AG基因型携带者的无病生存期（DFS）显著缩短，GG基因型是独立的预后因素（DFS：校正风险比[HR]=1.523，95%置信区间[CI]=1.012 - 2.293，P = 0.044；总生存期[OS]：校正HR = 2.321，95% CI = 1.281 - 4.204，P = 0.005）。此外，多因素降维分析（MDR）一致显示，3个选定的单核苷酸多态性（SNPs）与7个已知风险因素的组合是预测BC预后的最佳模型。荧光素酶报告基因检测显示，rs2494752的G等位基因显著增加了AKT1启动子活性。这些结果表明，PTEN基因rs701848和AKT1基因rs2494752多态性可能是评估BC易感性以及BC患者个体化环磷酰胺、表柔比星、氟尿嘧啶（CE(A)F）化疗反应和预后预测的候选药物基因组学因素。
