title: Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.
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.
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Jared R
authors.initials: JR
authors.lastname: Mayers
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.|Department of Epidemiology, Harvard School of Public Health, Boston, MA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Department of Biostatistics, Harvard School of Public Health, Boston, MA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Torrence
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Fiske
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
authors.forename: Chen
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Townsend
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Shelley S
authors.initials: SS
authors.lastname: Tworoger
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Thales
authors.initials: T
authors.lastname: Papagiannakopoulos
authors.affiliation: Division of Genomic Stability and DNA repair, Department of Radiation Oncology, Dana- Farber Cancer Institute, Boston, MA 02215.
authors.forename: Annan
authors.initials: A
authors.lastname: Yang
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Talya L
authors.initials: TL
authors.lastname: Dayton
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.|Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.|Department of Nutrition, Harvard School of Public Health, Boston, MA.
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.|Department of Nutrition, Harvard School of Public Health, Boston, MA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Rubinson
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Sesso
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.|Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System.
authors.forename: John Michael
authors.initials: JM
authors.lastname: Gaziano
authors.affiliation: University of Washington School of Nursing, Seattle, WA.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Cochrane
authors.affiliation: Departments of Epidemiology and Medicine, Brown University, Providence, RI.
authors.forename: Simin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Social and Preventive Medicine, University at Buffalo, SUNY, Buffalo, NY.
authors.forename: Jean
authors.initials: J
authors.lastname: Wactawski-Wende
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.|Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.affiliation: Departments of Oncology and Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
authors.affiliation: Division of Genomic Stability and DNA repair, Department of Radiation Oncology, Dana- Farber Cancer Institute, Boston, MA 02215.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Souza
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Pierce
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA.|Cardiology Division, Massachusetts General Hospital, and Harvard Medical School, Boston, MA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.|Broad Institute of MIT and Harvard University, Cambridge, MA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.|Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000597:Amino Acids, Branched-Chain / Q000097:blood*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood* / Q000209:etiology; D016022:Case-Control Studies; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000209:etiology; D011446:Prospective Studies; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000597:Amino Acids, Branched-Chain; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)