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Nat Med. 2014 Oct;20(10):1193-1198. doi: 10.1038/nm.3686. Epub 2014 Sep 28.

Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.

Author information

1
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
2
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
3
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
4
Department of Epidemiology, Harvard School of Public Health, Boston, MA.
5
Broad Institute of MIT and Harvard University, Cambridge, MA.
6
Department of Biostatistics, Harvard School of Public Health, Boston, MA.
7
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
8
Division of Genomic Stability and DNA repair, Department of Radiation Oncology, Dana- Farber Cancer Institute, Boston, MA 02215.
9
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
10
Department of Nutrition, Harvard School of Public Health, Boston, MA.
11
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
12
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System.
13
University of Washington School of Nursing, Seattle, WA.
14
Departments of Epidemiology and Medicine, Brown University, Providence, RI.
15
Department of Social and Preventive Medicine, University at Buffalo, SUNY, Buffalo, NY.
16
Departments of Oncology and Medicine, McGill University, Montreal, QC, Canada.
17
Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN.
18
Cardiology Division, Massachusetts General Hospital, and Harvard Medical School, Boston, MA.
19
Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
#
Contributed equally

Abstract

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

PMID:
25261994
PMCID:
PMC4191991
DOI:
10.1038/nm.3686
[Indexed for MEDLINE]
Free PMC Article

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