TY - JOUR
T1 - Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes
AU - Wang, Li E.
AU - Ma, Hongxia
AU - Hale, Katherine S.
AU - Yin, Ming
AU - Meyer, Larissa A.
AU - Liu, Hongliang
AU - Li, Jie
AU - Lu, Karen H.
AU - Hennessy, Bryan T.
AU - Li, Xuesong
AU - Spitz, Margaret R.
AU - Wei, Qingyi
AU - Mills, Gordon B.
N1 - Funding Information:
Acknowledgments This study was supported in part by National Institute of Health (NIH) grants ES11740 and CA131274 (Q. Wei), Stand Up to Cancer/American Association for Cancer Research Dream Team Translational Cancer Research Grant SU2C-AACR—DT0209, the Uterine SPORE CA098258 and the Kleberg Center For Molecular Markers (G. B. Mills), CA127219 (M. R. Spitz), and a Cancer Center Core grant from the National Cancer Institute to M. D. Anderson (CA016672). We would like to thank Joseph Celestino, Yang Li, Min Zhao, and Kejing Xu for preparing the DNA samples.
PY - 2012/3
Y1 - 2012/3
N2 - Purpose: 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). Conclusion: 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.
AB - Purpose: 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). Conclusion: 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.
KW - Endometrial cancer risk
KW - PI3K/PTEN/AKT/mTOR and RAS/RAF/ MEK/ERK pathways
KW - Polymorphisms
KW - Recurrence
KW - Survival
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U2 - 10.1007/s00432-011-1103-0
DO - 10.1007/s00432-011-1103-0
M3 - Article
C2 - 22146979
AN - SCOPUS:84859698883
SN - 0171-5216
VL - 138
SP - 377
EP - 385
JO - Journal of Cancer Research and Clinical Oncology
JF - Journal of Cancer Research and Clinical Oncology
IS - 3
ER -