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Journal of Cancer Research and Clinical Oncology

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01-03-2012 | Original Paper

Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes

Authors: Li-E Wang, Hongxia Ma, Katherine S. Hale, Ming Yin, Larissa A. Meyer, Hongliang Liu, Jie Li, Karen H. Lu, Bryan T. Hennessy, Xuesong Li, Margaret R. Spitz, Qingyi Wei, Gordon B. Mills

Published in: Journal of Cancer Research and Clinical Oncology | Issue 3/2012

Abstract

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.

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Title: Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes
Authors: Li-E Wang
Hongxia Ma
Katherine S. Hale
Ming Yin
Larissa A. Meyer
Hongliang Liu
Jie Li
Karen H. Lu
Bryan T. Hennessy
Xuesong Li
Margaret R. Spitz
Qingyi Wei
Gordon B. Mills
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: Journal of Cancer Research and Clinical Oncology / Issue 3/2012
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-011-1103-0

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