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. 2016 Jan 11;108(6):djv409.
doi: 10.1093/jnci/djv409. Print 2016 Jun.

Circulating Metabolites and Survival Among Patients With Pancreatic Cancer

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Free PMC article

Circulating Metabolites and Survival Among Patients With Pancreatic Cancer

Chen Yuan et al. J Natl Cancer Inst. .
Free PMC article

Abstract

Background: Pancreatic tumors cause changes in whole-body metabolism, but whether prediagnostic circulating metabolites predict survival is unknown.

Methods: We measured 82 metabolites by liquid chromatography-mass spectrometry in prediagnostic plasma from 484 pancreatic cancer case patients enrolled in four prospective cohort studies. Association of metabolites with survival was evaluated using Cox proportional hazards models adjusted for age, cohort, race/ethnicity, cancer stage, fasting time, and diagnosis year. After multiple-hypothesis testing correction, a P value of .0006 or less (.05/82) was considered statistically significant. Based on the results, we evaluated 33 tagging single-nucleotide polymorphisms (SNPs) in the ACO1 gene, requiring a P value of less than .002 (.05/33) for statistical significance. All statistical tests were two-sided.

Results: Two metabolites in the tricarboxylic acid (TCA) cycle--isocitrate and aconitate--were statistically significantly associated with survival. Participants in the highest vs lowest quintile had hazard ratios (HRs) for death of 1.89 (95% confidence interval [CI] = 1.06 to 3.35, Ptrend < .001) for isocitrate and 2.54 (95% CI = 1.42 to 4.54, Ptrend < .001) for aconitate. Isocitrate is interconverted with citrate via the intermediate aconitate in a reaction catalyzed by the enzyme aconitase 1 (ACO1). Therefore, we investigated the citrate to aconitate plus isocitrate ratio and SNPs in the ACO1 gene. The ratio was strongly associated with survival (P trend < .001) as was the SNP rs7874815 in the ACO1 gene (hazard ratio for death per minor allele = 1.37, 95% CI = 1.16 to 1.61, P < .001). Patients had an approximately three-fold hazard for death when possessing one or more minor alleles at rs7874851 and high aconitate or isocitrate.

Conclusions: Prediagnostic circulating levels of TCA cycle intermediates and inherited ACO1 genotypes were associated with survival among patients with pancreatic cancer.

Figures

Figure 1.
Figure 1.
Association of prediagnostic levels of plasma metabolites with overall survival among pancreatic cancer case patients. Two-sided P value of the log-transformed metabolite as a continuous variable in Cox regression models adjusted for age at diagnosis (years, continuous), cohort (Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative; also adjusts for sex), race/ethnicity (white, black, other, missing), stage at diagnosis (localized, locally advanced, metastatic, unknown), fasting time (<4, 4–8, 8–12, ≥12 hours, missing), and year of diagnosis (1984–1995, 1996–2005, 2006–2010). Solid line indicates the statistically significant P value threshold after Bonferroni correction for multiple-hypothesis testing (P value ≤ .0006, .05/82). Dashed line indicates P value of .05.
Figure 2.
Figure 2.
Overall survival among pancreatic cancer case patients by rs7874815 genotypes in ACO1. A table of the numbers of patients at risk in each group at various timepoints is given below the curves. Survival curves were generated by the Kaplan-Meier method, and the two-sided P value calculated using the log-rank test. CI = confidence interval; HR = hazard ratio; MAF = minor allele frequency.

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