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Genetic variations in the PI3K-PTEN-AKT-mTOR pathway are associated with distant metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy

View Article: PubMed Central - PubMed

ABSTRACT

Distant metastasis is the primary failure pattern of nasopharyngeal carcinoma(NPC) in intensity-modulated radiation therapy(IMRT) era. This study was conducted to find the impact of genetic variations in the phosphatidylinositol 3-kinase(PI3K)/phosphatase and tensin homologue(PTEN)/v-akt murine thymoma viral oncogene homologue(AKT)/mammalian target of rapamycin(mTOR) pathway on the risk of distant metastasis in NPC. We genotyped 16 single-nucleotide polymorphisms(SNPs) in five core genes in this pathway from 496 patients treated by IMRT with or without chemotherapy. The relationships between genetic polymorphisms and distant progression were evaluated. We observed that two loci in the AKT1 gene(rs3803300 and rs2494738 alone or combined) were associated with prognosis, with patients carrying at least one variant allele had significantly reduced risk of distant failure, especially in N2-3 group. In addition, we found that genetic variation may had some joint effect with N classification in recursive-partitioning analysis(RPA) analysis, with which patients were stratified into four different risk subgroups (RPA model): RPA1(low risk), RPA2(moderate risk), RPA3(high risk) and RPA4(highest risk). Our findings suggested that genetic variations within the PI3K signaling pathway modulate the development and invasion of NPC patients. Further research is needed to replicate the study in other centers and races, and to unravel the functional significance of these polymorphisms.

No MeSH data available.


(A) Prognostic grouping by recursive-partitioning analysis(RPA) analysis showed the interactions between SNPs and N classification; (B) Kaplan-Meier curves of DMFS for four different RPA groups; (C) The prognostic effect of RPA grouping on DMFS by multivariate analysis.
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f2: (A) Prognostic grouping by recursive-partitioning analysis(RPA) analysis showed the interactions between SNPs and N classification; (B) Kaplan-Meier curves of DMFS for four different RPA groups; (C) The prognostic effect of RPA grouping on DMFS by multivariate analysis.

Mentions: In current series, only N classification and unfavorable genotype were identified as factors strongly related to risk of distant failure. RPA for DMFS was conducted with these two factors to derive RPA groups objectively. The RPA algorithm finally classified these patients into four RPA groups: RPA1 (low risk: N0-1, without unfavorable genotype), RPA2 (moderate risk: N0-1, with at least one unfavorable genotype), RPA3 (high risk: N2-3, without unfavorable genotype) and RPA4 (highest risk: N2-3, with at least one unfavorable genotype), with patients in RPA 4 had the highest risk of distant failure (Fig. 2). Multivariate analysis, adjusted for gender, age, T classification and treatment confirmed that higher RPA group conferred an increased distant metastatic risk (HR = 1.783; 95% CI = 1.364–2.331; P < 0.001).


Genetic variations in the PI3K-PTEN-AKT-mTOR pathway are associated with distant metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy
(A) Prognostic grouping by recursive-partitioning analysis(RPA) analysis showed the interactions between SNPs and N classification; (B) Kaplan-Meier curves of DMFS for four different RPA groups; (C) The prognostic effect of RPA grouping on DMFS by multivariate analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120316&req=5

f2: (A) Prognostic grouping by recursive-partitioning analysis(RPA) analysis showed the interactions between SNPs and N classification; (B) Kaplan-Meier curves of DMFS for four different RPA groups; (C) The prognostic effect of RPA grouping on DMFS by multivariate analysis.
Mentions: In current series, only N classification and unfavorable genotype were identified as factors strongly related to risk of distant failure. RPA for DMFS was conducted with these two factors to derive RPA groups objectively. The RPA algorithm finally classified these patients into four RPA groups: RPA1 (low risk: N0-1, without unfavorable genotype), RPA2 (moderate risk: N0-1, with at least one unfavorable genotype), RPA3 (high risk: N2-3, without unfavorable genotype) and RPA4 (highest risk: N2-3, with at least one unfavorable genotype), with patients in RPA 4 had the highest risk of distant failure (Fig. 2). Multivariate analysis, adjusted for gender, age, T classification and treatment confirmed that higher RPA group conferred an increased distant metastatic risk (HR = 1.783; 95% CI = 1.364–2.331; P < 0.001).

View Article: PubMed Central - PubMed

ABSTRACT

Distant metastasis is the primary failure pattern of nasopharyngeal carcinoma(NPC) in intensity-modulated radiation therapy(IMRT) era. This study was conducted to find the impact of genetic variations in the phosphatidylinositol 3-kinase(PI3K)/phosphatase and tensin homologue(PTEN)/v-akt murine thymoma viral oncogene homologue(AKT)/mammalian target of rapamycin(mTOR) pathway on the risk of distant metastasis in NPC. We genotyped 16 single-nucleotide polymorphisms(SNPs) in five core genes in this pathway from 496 patients treated by IMRT with or without chemotherapy. The relationships between genetic polymorphisms and distant progression were evaluated. We observed that two loci in the AKT1 gene(rs3803300 and rs2494738 alone or combined) were associated with prognosis, with patients carrying at least one variant allele had significantly reduced risk of distant failure, especially in N2-3 group. In addition, we found that genetic variation may had some joint effect with N classification in recursive-partitioning analysis(RPA) analysis, with which patients were stratified into four different risk subgroups (RPA model): RPA1(low risk), RPA2(moderate risk), RPA3(high risk) and RPA4(highest risk). Our findings suggested that genetic variations within the PI3K signaling pathway modulate the development and invasion of NPC patients. Further research is needed to replicate the study in other centers and races, and to unravel the functional significance of these polymorphisms.

No MeSH data available.