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Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population.

ABSTRACT: Genetic variations in a PTEN/AKT/mTOR signaling axis may influence cellular functions including cell growth, proliferation and apoptosis, and then increase the individual's risk of cancer. Accordingly, we explore the association between single nucleotide polymorphisms (SNPs) of these genes and prostate cancer (PCa) in our Chinese population.Subjects were recruited from 666 PCa patients and 708 cancer-free controls, and eight SNPs in the PTEN/AKT/mTOR axis were determined by the TaqMan assay. Odds ratios (OR) and 95% confidence intervals (95% CI) were evaluated by logistic regression.We observed significant associations between PCa risk and mTOR rs2295080 [P?=?0.027, OR?=?0.85, 95%CI?=?0.74-0.98], and AKT2 rs7254617 (P?=?0.003, OR?=?1.35, 95%CI?=?1.11-1.64). When estimated these two SNPs together, the combined genotypes with 2-4 risk alleles (rs2295080 T and rs7254617 A alleles) were associated with an increased risk of PCa compared with 0-1 risk alleles, which was more pronounced among subgroups of age >71 years, smokers, drinkers and no family history of cancer. Results of stratified analyses by cliniopathological parameters revealed that the frequencies of the combined genotypes with 2-4 risk alleles in advanced stage were significantly higher than in localized stage (P?=?0.022), but there was no significant association in Gleason score and PSA level.Our results indicate, for the first time that the two variants in AKT2 and mTOR, particularly the joint genotypes with 2-4 risk alleles may influence PCa susceptibility and progression in Chinese, and the association appeared to be more strong in the subgroup of smokers and drinkers.

SUBMITTER: Chen J

PROVIDER: S-EPMC3399895 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population.

Chen Jiawei J Shao Pengfei P Cao Qiang Q Li Pu P Li Jie J Cai Hongzhou H Zhu Jian J Wang Meilin M Zhang Zhengdong Z Qin Chao C Yin Changjun C

PloS one 20120718 7

<h4>Background</h4>Genetic variations in a PTEN/AKT/mTOR signaling axis may influence cellular functions including cell growth, proliferation and apoptosis, and then increase the individual's risk of cancer. Accordingly, we explore the association between single nucleotide polymorphisms (SNPs) of these genes and prostate cancer (PCa) in our Chinese population.<h4>Methods</h4>Subjects were recruited from 666 PCa patients and 708 cancer-free controls, and eight SNPs in the PTEN/AKT/mTOR axis were ...[more]

PMID: 22815832

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Project description:PurposeThe phosphoinositide-3-kinase (PI3K), phosphatase and tensin homolog (PTEN), v-akt murine thymoma viral oncogene homolog (AKT), and mammalian target of rapamycin (mTOR) signaling pathway has been implicated in resistance to several chemotherapeutic agents. In this retrospective study, we determined whether common genetic variations in this pathway are associated with clinical outcomes in esophageal cancer patients with adenocarcinoma or squamous cell carcinoma who have undergone chemoradiotherapy and surgery.Patients and methodsSixteen tagging single nucleotide polymorphisms (SNPs) in PIK3CA, PTEN, AKT1, AKT2, and FRAP1 (encoding mTOR) were genotyped in these patients and analyzed for associations with response to therapy, survival, and recurrence.ResultsWe observed an increased recurrence risk with genetic variations in AKT1 and AKT2 (hazard ratio [HR], 2.21; 95% CI, 1.06 to 4.60; and HR, 3.30; 95% CI, 1.64 to 6.66, respectively). This effect was magnified with an increasing number of AKT adverse genotypes. In contrast, a predictable protective effect by PTEN genetic variants on recurrence was evident. Survival tree analysis identified higher-order interactions that resulted in variation in recurrence-free survival from 12 to 42 months, depending on the combination of SNPs. Genetic variations in AKT1, AKT2, and FRAP1 were associated with survival. Patients homozygous for either of the FRAP1 SNPs assayed had a more than three-fold increased risk of death. Two genes--AKT2 and FRAP1--were associated with a poor treatment response, while a better response was associated with heterozygosity for AKT1:rs3803304 (odds ratio, 0.50; 95% CI, 0.25 to 0.99).ConclusionThese results suggest that common genetic variations in this pathway modulate clinical outcomes in patients who undergo chemoradiotherapy. With further validation, these results may be used to build a model of individualized therapy for the selection of the optimal chemotherapeutic regimen.

Dataset Information

Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population.

Publications

Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population.

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