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

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 Mills

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)377-385
Number of pages9
JournalJournal of Cancer Research and Clinical Oncology
Volume138
Issue number3
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Endometrial Neoplasms
Single Nucleotide Polymorphism
Odds Ratio
Recurrence
Survival
MAP Kinase Signaling System
Carcinogenesis
Genotype
Regression Analysis

Keywords

  • Endometrial cancer risk
  • PI3K/PTEN/AKT/mTOR and RAS/RAF/ MEK/ERK pathways
  • Polymorphisms
  • Recurrence
  • Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: Journal of Cancer Research and Clinical Oncology, Vol. 138, No. 3, 01.03.2012, p. 377-385.

Research output: Contribution to journalArticle

Wang, LE, Ma, H, Hale, KS, Yin, M, Meyer, LA, Liu, H, Li, J, Lu, KH, Hennessy, BT, Li, X, Spitz, MR, Wei, Q & Mills, G 2012, 'Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes', Journal of Cancer Research and Clinical Oncology, vol. 138, no. 3, pp. 377-385. https://doi.org/10.1007/s00432-011-1103-0
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. / Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes. In: Journal of Cancer Research and Clinical Oncology. 2012 ; Vol. 138, No. 3. pp. 377-385.
@article{1b2f0467e387497a90ea1e5a22d05efc,
title = "Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes",
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.",
keywords = "Endometrial cancer risk, PI3K/PTEN/AKT/mTOR and RAS/RAF/ MEK/ERK pathways, Polymorphisms, Recurrence, Survival",
author = "Wang, {Li E.} and Hongxia Ma and Hale, {Katherine S.} and Ming Yin and Meyer, {Larissa A.} and Hongliang Liu and Jie Li and Lu, {Karen H.} and Hennessy, {Bryan T.} and Xuesong Li and Spitz, {Margaret R.} and Qingyi Wei and Gordon Mills",
year = "2012",
month = "3",
day = "1",
doi = "10.1007/s00432-011-1103-0",
language = "English (US)",
volume = "138",
pages = "377--385",
journal = "Journal of Cancer Research and Clinical Oncology",
issn = "0171-5216",
publisher = "Springer Verlag",
number = "3",

}

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

PY - 2012/3/1

Y1 - 2012/3/1

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

UR - http://www.scopus.com/inward/record.url?scp=84859698883&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859698883&partnerID=8YFLogxK

U2 - 10.1007/s00432-011-1103-0

DO - 10.1007/s00432-011-1103-0

M3 - Article

VL - 138

SP - 377

EP - 385

JO - Journal of Cancer Research and Clinical Oncology

JF - Journal of Cancer Research and Clinical Oncology

SN - 0171-5216

IS - 3

ER -