title: Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. lwang@mdanderson.org
authors.forename: Li-E
authors.initials: LE
authors.lastname: Wang
authors.forename: Hongxia
authors.initials: H
authors.lastname: Ma
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Hale
authors.forename: Ming
authors.initials: M
authors.lastname: Yin
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Meyer
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.forename: Xuesong
authors.initials: X
authors.lastname: Li
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008875:Middle Aged; D016017:Odds Ratio; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D016896:Treatment Outcome; D048490:raf Kinases / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; C494929:PTEN protein, human