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Functional polymorphisms in the NPAS2 gene are associated with overall survival in transcatheter arterial chemoembolization-treated hepatocellular carcinoma patients.

Yuan P, Wang S, Zhou F, Wan S, Yang Y, Huang X, Zhang Z, Zhu Y, Zhang H, Xing J - Cancer Sci. (2014)

Bottom Line: We found that two SNPs, rs1053096 and rs2305160, in the NPAS2 gene showed significant associations with overall death risk in HCC patients in the recessive model (hazard ratio [HR] = 1.48; 95% confidence interval [CI], 1.13-1.94; P = 0.004) and in the dominant model (HR = 1.63; 95% CI, 1.29-2.07; P < 0.001), respectively.Moreover, we observed a cumulative effect of these two SNPs on HCC overall survival, indicating a significant trend of increasing death risk with increasing number of unfavorable genotypes (P for trend < 0.001).Our results for the first time suggest that NPAS2 gene polymorphisms may serve as an independent prognostic marker for HCC patients treated with TACE.

View Article: PubMed Central - PubMed

Affiliation: Department of Pain Management, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.

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Kaplan–Meier plots of overall survival in Chinese patients with hepatocellular carcinoma treated with transcatheter arterial chemoembolization. Overall survival analysis of patients with single nucleotide polymorphisms (SNPs) rs1053096 (a) and rs2305160 (b) in the NPAS2 gene. VV, homozygous variant; WV, heterozygous variant; WW, homozygous wild-type. (c) Cumulative effect of unfavorable genotypes. Group 1, no unfavorable genotypes; Group 2, one unfavorable genotype; Group 3, two unfavorable genotypes. (d) Haplotype analysis of combined SNPs rs1053096 and rs2305160. (e) Diplotype analysis of combined SNPs rs1053096 and rs2305160. The differences between indicated groups in each analysis were compared by the log–rank test.
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fig01: Kaplan–Meier plots of overall survival in Chinese patients with hepatocellular carcinoma treated with transcatheter arterial chemoembolization. Overall survival analysis of patients with single nucleotide polymorphisms (SNPs) rs1053096 (a) and rs2305160 (b) in the NPAS2 gene. VV, homozygous variant; WV, heterozygous variant; WW, homozygous wild-type. (c) Cumulative effect of unfavorable genotypes. Group 1, no unfavorable genotypes; Group 2, one unfavorable genotype; Group 3, two unfavorable genotypes. (d) Haplotype analysis of combined SNPs rs1053096 and rs2305160. (e) Diplotype analysis of combined SNPs rs1053096 and rs2305160. The differences between indicated groups in each analysis were compared by the log–rank test.

Mentions: We assessed the association between each individual SNP and clinical outcome using the multivariate Cox proportional hazard model with adjustment for age, sex, HBV infection, PVTT, TNM stage, serum AFP, and treatment under dominant, additive, and recessive models (Tables 2, S1). We found that rs1053096 was significantly associated with HCC OS (Table 2). Compared to the WW and WV of rs1053096, the VV conferred a significant increased risk of death (HR = 1.48; 95% CI, 1.13–1.94; P = 0.004) in HCC patients. In addition, compared to the WW of rs2305160, patients carrying at least one variant allele (WV + VV) had a significant increased risk of death (HR = 1.63; 95% CI, 1.29–2.07; P < 0.001) (Table 2). Kaplan–Meier curve analysis showed that there was no significant difference in OS among patients with different genotypes in each SNP except rs2305160 (Fig. S1). Further analysis showed that patients with VV genotype in rs1053096 had better OS than those with WW or WV genotype (Fig. 1a), whereas patients with WW genotype in rs2305160 had worse OS than those with WW or WV genotype (Fig. 1b). To further evaluate the predictive effect on HCC outcome of SNPs in the NPAS2 gene, we carried out a stratified analysis (Table 3). The death risk conferred by rs1053096 remained significant in patients who were more than 53 years old (HR = 1.64; 95% CI, 1.11–2.41, P = 0.01), in male patients (HR = 1.44; 95% CI, 1.08–1.92, P = 0.01), in patients who were HBsAg positive (HR = 1.46; 95% CI, 1.10–1.94, P = 0.01), in patients without PVTT (HR = 1.45; 95% CI, 1.04–2.01, P = 0.03), in patients with TNM stage I and II disease (HR = 1.53; 95% CI, 1.01–2.32, P = 0.05), and in patients treated by TACE alone (HR = 1.56; 95% CI, 1.17–2.08, P = 0.003). Similar results were observed with rs2305160. In particular, P-values were <0.001 in male patients (HR = 1.69; 95% CI, 1.31–2.17), in HBsAg-positive patients (HR = 1.57; 95% CI, 1.22–2.03), those with stage III and IV disease (HR = 1.94; 95% CI, 1.41–2.67), in patients with increased serum AFP (HR = 1.76; 95% CI, 1.28–2.42), and in patients treated with TACE alone (HR = 1.76; 95% CI, 1.37–2.26).


Functional polymorphisms in the NPAS2 gene are associated with overall survival in transcatheter arterial chemoembolization-treated hepatocellular carcinoma patients.

Yuan P, Wang S, Zhou F, Wan S, Yang Y, Huang X, Zhang Z, Zhu Y, Zhang H, Xing J - Cancer Sci. (2014)

Kaplan–Meier plots of overall survival in Chinese patients with hepatocellular carcinoma treated with transcatheter arterial chemoembolization. Overall survival analysis of patients with single nucleotide polymorphisms (SNPs) rs1053096 (a) and rs2305160 (b) in the NPAS2 gene. VV, homozygous variant; WV, heterozygous variant; WW, homozygous wild-type. (c) Cumulative effect of unfavorable genotypes. Group 1, no unfavorable genotypes; Group 2, one unfavorable genotype; Group 3, two unfavorable genotypes. (d) Haplotype analysis of combined SNPs rs1053096 and rs2305160. (e) Diplotype analysis of combined SNPs rs1053096 and rs2305160. The differences between indicated groups in each analysis were compared by the log–rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4317913&req=5

fig01: Kaplan–Meier plots of overall survival in Chinese patients with hepatocellular carcinoma treated with transcatheter arterial chemoembolization. Overall survival analysis of patients with single nucleotide polymorphisms (SNPs) rs1053096 (a) and rs2305160 (b) in the NPAS2 gene. VV, homozygous variant; WV, heterozygous variant; WW, homozygous wild-type. (c) Cumulative effect of unfavorable genotypes. Group 1, no unfavorable genotypes; Group 2, one unfavorable genotype; Group 3, two unfavorable genotypes. (d) Haplotype analysis of combined SNPs rs1053096 and rs2305160. (e) Diplotype analysis of combined SNPs rs1053096 and rs2305160. The differences between indicated groups in each analysis were compared by the log–rank test.
Mentions: We assessed the association between each individual SNP and clinical outcome using the multivariate Cox proportional hazard model with adjustment for age, sex, HBV infection, PVTT, TNM stage, serum AFP, and treatment under dominant, additive, and recessive models (Tables 2, S1). We found that rs1053096 was significantly associated with HCC OS (Table 2). Compared to the WW and WV of rs1053096, the VV conferred a significant increased risk of death (HR = 1.48; 95% CI, 1.13–1.94; P = 0.004) in HCC patients. In addition, compared to the WW of rs2305160, patients carrying at least one variant allele (WV + VV) had a significant increased risk of death (HR = 1.63; 95% CI, 1.29–2.07; P < 0.001) (Table 2). Kaplan–Meier curve analysis showed that there was no significant difference in OS among patients with different genotypes in each SNP except rs2305160 (Fig. S1). Further analysis showed that patients with VV genotype in rs1053096 had better OS than those with WW or WV genotype (Fig. 1a), whereas patients with WW genotype in rs2305160 had worse OS than those with WW or WV genotype (Fig. 1b). To further evaluate the predictive effect on HCC outcome of SNPs in the NPAS2 gene, we carried out a stratified analysis (Table 3). The death risk conferred by rs1053096 remained significant in patients who were more than 53 years old (HR = 1.64; 95% CI, 1.11–2.41, P = 0.01), in male patients (HR = 1.44; 95% CI, 1.08–1.92, P = 0.01), in patients who were HBsAg positive (HR = 1.46; 95% CI, 1.10–1.94, P = 0.01), in patients without PVTT (HR = 1.45; 95% CI, 1.04–2.01, P = 0.03), in patients with TNM stage I and II disease (HR = 1.53; 95% CI, 1.01–2.32, P = 0.05), and in patients treated by TACE alone (HR = 1.56; 95% CI, 1.17–2.08, P = 0.003). Similar results were observed with rs2305160. In particular, P-values were <0.001 in male patients (HR = 1.69; 95% CI, 1.31–2.17), in HBsAg-positive patients (HR = 1.57; 95% CI, 1.22–2.03), those with stage III and IV disease (HR = 1.94; 95% CI, 1.41–2.67), in patients with increased serum AFP (HR = 1.76; 95% CI, 1.28–2.42), and in patients treated with TACE alone (HR = 1.76; 95% CI, 1.37–2.26).

Bottom Line: We found that two SNPs, rs1053096 and rs2305160, in the NPAS2 gene showed significant associations with overall death risk in HCC patients in the recessive model (hazard ratio [HR] = 1.48; 95% confidence interval [CI], 1.13-1.94; P = 0.004) and in the dominant model (HR = 1.63; 95% CI, 1.29-2.07; P < 0.001), respectively.Moreover, we observed a cumulative effect of these two SNPs on HCC overall survival, indicating a significant trend of increasing death risk with increasing number of unfavorable genotypes (P for trend < 0.001).Our results for the first time suggest that NPAS2 gene polymorphisms may serve as an independent prognostic marker for HCC patients treated with TACE.

View Article: PubMed Central - PubMed

Affiliation: Department of Pain Management, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.

Show MeSH
Related in: MedlinePlus