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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

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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.


Kaplan-Meier curves of DMFS in NPC patients with different genotypes of (A) AKT1: rs3803300 and (B) AKT1:rs2494738; (C) Kaplan-Meier curves of DMFS in NPC patients with or without unfavorable genotypes.
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f1: Kaplan-Meier curves of DMFS in NPC patients with different genotypes of (A) AKT1: rs3803300 and (B) AKT1:rs2494738; (C) Kaplan-Meier curves of DMFS in NPC patients with or without unfavorable genotypes.

Mentions: Of the 16 SNPs, only two SNPs- AKT1: rs3803300 and AKT1:rs2494738-were found to be significantly associated with DMFS after MVA (Table 4). AKT1: rs3803300, as detailed in Table 4, resulted in significantly inferior DMFS for patients with wild-type genotype compared with those with one or two variant alleles (Fig. 1) (74.5% vs. 86.7%, P = 0.025). The same result was verified after stratifying by patient-, tumor- and treatment-related factors (HR = 0.536; 95% CI = 0.292–0.986; P = 0.045). Patients carrying at least one variant allele for AKT1: rs2494738 had a better DMFS than those with wile-type genotype (86.9% vs. 80.5%, P = 0.106) (Fig. 1), this trend became significant after adjusting by gender, age, treatment, T- and N-category (HR = 0.530; 95% CI = 0.302–0.929; P = 0.027).


Genetic variations in the PI3K-PTEN-AKT-mTOR pathway are associated with distant metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy
Kaplan-Meier curves of DMFS in NPC patients with different genotypes of (A) AKT1: rs3803300 and (B) AKT1:rs2494738; (C) Kaplan-Meier curves of DMFS in NPC patients with or without unfavorable genotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5120316&req=5

f1: Kaplan-Meier curves of DMFS in NPC patients with different genotypes of (A) AKT1: rs3803300 and (B) AKT1:rs2494738; (C) Kaplan-Meier curves of DMFS in NPC patients with or without unfavorable genotypes.
Mentions: Of the 16 SNPs, only two SNPs- AKT1: rs3803300 and AKT1:rs2494738-were found to be significantly associated with DMFS after MVA (Table 4). AKT1: rs3803300, as detailed in Table 4, resulted in significantly inferior DMFS for patients with wild-type genotype compared with those with one or two variant alleles (Fig. 1) (74.5% vs. 86.7%, P = 0.025). The same result was verified after stratifying by patient-, tumor- and treatment-related factors (HR = 0.536; 95% CI = 0.292–0.986; P = 0.045). Patients carrying at least one variant allele for AKT1: rs2494738 had a better DMFS than those with wile-type genotype (86.9% vs. 80.5%, P = 0.106) (Fig. 1), this trend became significant after adjusting by gender, age, treatment, T- and N-category (HR = 0.530; 95% CI = 0.302–0.929; P = 0.027).

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.