Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes.
Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes.
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DOI：
10.1007/s00432-011-1103-0
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发表时间：
2012-03
影响因子：
3.6
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Wang, Li-E;Ma, Hongxia;Hale, Katherine S.;Yin, Ming;Meyer, Larissa A.;Liu, Hongliang;Li, Jie;Lu, Karen H.;Hennessy, Bryan T.;Li, Xuesong;Spitz, Margaret R.;Wei, Qingyi;Mills, Gordon B.
关键词：
磷脂酰肌醇3-激酶（PI 3 K）/PTEN/AKT/mTOR和Ras/Raf/MEK/ERK通路与子宫内膜肿瘤发生有关。在这个候选通路分析中，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果之间的关联。我们使用Sequenom基因分型平台对115名子宫内膜癌患者和230名无癌妇女的11个关键基因（AKT 1、AKT 2、AKT 3、BRAF、FRAP 1、KRAS、PDPK 1、PIK 3CA、PIK 3CB、PIK 3R 1和PTEN）中的48个潜在功能性SNP进行基因分型，以评估其与子宫内膜癌风险、生存率和复发的相关性。我们发现以下内容：（1）PIK 3CA rs6443624和rs 9838411变异体在显性模型中临界或显著降低子宫内膜癌的风险（校正比值比[OR]，0.62; 95%CI，0.39-1.00和0.59; 95%CI，0.36-0.95）。此外，这两个基因座在子宫内膜癌的风险之间存在统计学显著的乘法交互作用（Pint = 0.036）。相反，AKT 1 rs 2498801基因型显著增加了子宫内膜癌的风险（隐性模型中调整的OR为1.94; 95%CI为1.02-3.67）。(2)在考克斯回归分析中，三个SNP（PIK 3R 1 rs 1862162，AKT 2 rs 892119和PIK 3CA rs 2699887）显示与子宫内膜癌患者的生存率显著相关。(3)KRAS rs7312175和PIK 3CA rs6443624单独和以位点剂量方式组合对子宫内膜癌复发具有显著影响（校正的P趋势= 0.003）。这些结果表明，这些通路中的常见遗传变异可能会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。
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 (Pint = 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 Ptrend = 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.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
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