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

Circulating Metabolites and Survival Among Patients With Pancreatic Cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CY, ZRQ, DAR, KN, SO, MGVH, CSF, BMW); Broad Institute of MIT and Harvard University, Cambridge, MA (CBC, MGVH); Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China (CW); Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (JRM, MET, MGVH); Department of Epidemiology (PK, SST, ELG, SO, MJS, JM, HDS, JEM), Department of Biostatistics (PK), and Department of Nutrition (ELG, MJS), Harvard School of Public Health, Boston, MA; Department of Pathology (SO), and Channing Division of Network Medicine (MKT, SST, YB, ELG, MJS, JM, JEM, CSF) and Division of Preventive Medicine (JMG, HDS, JEM), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (MZ, LTA); Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (JMG); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (GLA); University of Washington School of Nursing, Seattle, WA (BBC); Division of Genomic Stability and DNA repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA (ACK).
2
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CY, ZRQ, DAR, KN, SO, MGVH, CSF, BMW); Broad Institute of MIT and Harvard University, Cambridge, MA (CBC, MGVH); Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China (CW); Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (JRM, MET, MGVH); Department of Epidemiology (PK, SST, ELG, SO, MJS, JM, HDS, JEM), Department of Biostatistics (PK), and Department of Nutrition (ELG, MJS), Harvard School of Public Health, Boston, MA; Department of Pathology (SO), and Channing Division of Network Medicine (MKT, SST, YB, ELG, MJS, JM, JEM, CSF) and Division of Preventive Medicine (JMG, HDS, JEM), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (MZ, LTA); Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (JMG); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (GLA); University of Washington School of Nursing, Seattle, WA (BBC); Division of Genomic Stability and DNA repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA (ACK). bwolpin@partners.org.

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.

PMID:
26755275
PMCID:
PMC4849356
DOI:
10.1093/jnci/djv409
[Indexed for MEDLINE]
Free PMC Article

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