Circulating Metabolites and Survival Among Patients With Pancreatic Cancer

Chen Yuan; Clary B Clish; Chen Wu; Jared R Mayers; Peter Kraft; Mary K Townsend; Mingfeng Zhang; Shelley S Tworoger; Ying Bao; Zhi Rong Qian; Douglas A Rubinson; Kimmie Ng; Edward L Giovannucci; Shuji Ogino; Meir J Stampfer; John Michael Gaziano; Jing Ma; Howard D Sesso; Garnet L Anderson; Barbara B Cochrane; JoAnn E Manson; Margaret E Torrence; Alec C Kimmelman; Laufey T Amundadottir; Matthew G Vander Heiden; Charles S Fuchs; Brian M Wolpin

doi:10.1093/jnci/djv409

Circulating Metabolites and Survival Among Patients With Pancreatic Cancer

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

Authors

Chen Yuan¹, Clary B Clish¹, Chen Wu¹, Jared R Mayers¹, Peter Kraft¹, Mary K Townsend¹, Mingfeng Zhang¹, Shelley S Tworoger¹, Ying Bao¹, Zhi Rong Qian¹, Douglas A Rubinson¹, Kimmie Ng¹, Edward L Giovannucci¹, Shuji Ogino¹, Meir J Stampfer¹, John Michael Gaziano¹, Jing Ma¹, Howard D Sesso¹, Garnet L Anderson¹, Barbara B Cochrane¹, JoAnn E Manson¹, Margaret E Torrence¹, Alec C Kimmelman¹, Laufey T Amundadottir¹, Matthew G Vander Heiden¹, Charles S Fuchs¹, Brian M Wolpin²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aconitic Acid / blood
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor / blood*
Female
Follow-Up Studies
Genotype
Humans
Iron Regulatory Protein 1 / blood*
Iron Regulatory Protein 1 / genetics*
Isocitrates / blood
Kaplan-Meier Estimate
Male
Middle Aged
Nurses
Odds Ratio
Pancreatic Neoplasms / blood*
Pancreatic Neoplasms / diagnosis
Pancreatic Neoplasms / mortality*
Polymorphism, Single Nucleotide*
Proportional Hazards Models
Prospective Studies
Tricarboxylic Acids / blood*
United States / epidemiology
Women's Health

Substances

Biomarkers, Tumor
Isocitrates
Tricarboxylic Acids
Aconitic Acid
isocitric acid
Iron Regulatory Protein 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding