Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
J Cancer Res Clin Oncol. 2012 Mar;138(3):377-85. doi: 10.1007/s00432-011-1103-0. Epub 2011 Dec 7.
The phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mTOR and Ras/Raf/MEK/ERK pathways have been implicated in endometrial tumorigenesis. In this candidate pathway analysis, we investigated associations between genetic variations in these two pathways and both risk and clinical outcomes of endometrial cancer.
We genotyped a total of 48 potentially functional SNPs in 11 key genes (AKT1, AKT2, AKT3, BRAF, FRAP1, KRAS, PDPK1, PIK3CA, PIK3CB, PIK3R1, and PTEN) with the Sequenom genotyping platform in 115 endometrial cancer patients and 230 cancer-free women to evaluate their associations with risk, survival, and recurrence of endometrial cancer.
We found the following: (1) PIK3CA rs6443624 and rs9838411 variants either borderline or significantly decreased risk of endometrial cancer in a dominant model (adjusted odds ratio [OR], 0.62; 95% CI, 0.39-1.00 and 0.59; 95% CI, 0.36-0.95, respectively). Furthermore, there was a statistically significant multiplicative interaction (P (int) = 0.036) between these two loci in risk of endometrial cancer. In contrast, the AKT1 rs2498801 genotype significantly increased risk of endometrial cancer (adjusted OR, 1.94; 95% CI, 1.02-3.67 in a recessive model). (2) In Cox regression analyses, three SNPs (PIK3R1 rs1862162, AKT2 rs892119, and PIK3CA rs2699887) showed significant associations with survival of endometrial cancer patients. (3) KRAS rs7312175 and PIK3CA rs6443624 had significant effects on recurrence of endometrial cancer individually and combined in a locus-dosage manner (adjusted P (trend) = 0.003).
These results suggest that common genetic variations in these pathways may modulate risk and clinical outcomes of endometrial cancer. Further replication and functional studies are needed to confirm these findings.
磷脂酰肌醇 3-激酶（PI3K）/PTEN/AKT/mTOR 和 Ras/Raf/MEK/ERK 通路与子宫内膜肿瘤的发生有关。在本候选通路分析中，我们研究了这两个通路中的遗传变异与子宫内膜癌的风险和临床结局之间的关系。
我们使用 Sequenom 基因分型平台对 115 名子宫内膜癌患者和 230 名无癌症女性的 11 个关键基因（AKT1、AKT2、AKT3、BRAF、FRAP1、KRAS、PDPK1、PIK3CA、PIK3CB、PIK3R1 和 PTEN）中的 48 个潜在功能 SNP 进行了总计基因型分析，以评估它们与子宫内膜癌的风险、生存和复发的关系。
我们发现：（1）PIK3CA rs6443624 和 rs9838411 变体在显性模型中具有边缘或显著降低子宫内膜癌风险的作用（调整后的优势比 [OR]，0.62；95%CI，0.39-1.00 和 0.59；95%CI，0.36-0.95）。此外，这两个位点在子宫内膜癌风险中存在统计学上显著的乘法交互作用（P (int) = 0.036）。相反，AKT1 rs2498801 基因型显著增加了子宫内膜癌的风险（调整后的 OR，1.94；95%CI，1.02-3.67，在隐性模型中）。（2）在 Cox 回归分析中，三个 SNP（PIK3R1 rs1862162、AKT2 rs892119 和 PIK3CA rs2699887）与子宫内膜癌患者的生存显著相关。（3）KRAS rs7312175 和 PIK3CA rs6443624 单独以及以基因座剂量方式对子宫内膜癌的复发具有显著影响（调整后的 P (trend) = 0.003）。
这些结果表明，这些通路中的常见遗传变异可能调节子宫内膜癌的风险和临床结局。需要进一步的复制和功能研究来证实这些发现。
