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Nat Med DOI:10.1038/nm.3686

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

Publication TypeJournal Article
Year of Publication2014
AuthorsMayers, JR, Wu, C, Clish, CB, Kraft, P, Torrence, ME, Fiske, BP, Yuan, C, Bao, Y, Townsend, MK, Tworoger, SS, Davidson, SM, Papagiannakopoulos, T, Yang, A, Dayton, TL, Ogino, S, Stampfer, MJ, Giovannucci, EL, Qian, ZRong, Rubinson, DA, Ma, J, Sesso, HD, Gaziano, JM, Cochrane, BB, Liu, S, Wactawski-Wende, J, Manson, JAE, Pollak, MN, Kimmelman, AC, Souza, A, Pierce, K, Wang, TJ, Gerszten, RE, Fuchs, CS, Heiden, MGVander, Wolpin, BM
JournalNat Med
Volume20
Issue10
Pages1193-8
Date Published2014 Oct
ISSN1546-170X
KeywordsAdult, Aged, Aged, 80 and over, Amino Acids, Branched-Chain, Animals, Carcinoma, Pancreatic Ductal, Case-Control Studies, Cohort Studies, Disease Models, Animal, Disease Progression, Female, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Pancreatic Neoplasms, Prospective Studies, Proto-Oncogene Proteins p21(ras), Risk Factors, Time Factors
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.

URLhttp://dx.doi.org/10.1038/nm.3686
DOI10.1038/nm.3686
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25261994?dopt=Abstract

Alternate JournalNat. Med.
PubMed ID25261994
PubMed Central IDPMC4191991
Grant ListT32 GM007287 / GM / NIGMS NIH HHS / United States
F30 CA183474 / CA / NCI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
HHSN271201100004C / / PHS HHS / United States
CA 97193 / CA / NCI NIH HHS / United States
R01 CA168653 / CA / NCI NIH HHS / United States
HHSN268201100001C / / PHS HHS / United States
HL 26490 / HL / NHLBI NIH HHS / United States
P01 CA055075 / CA / NCI NIH HHS / United States
R01 DK081572 / DK / NIDDK NIH HHS / United States
R01 HL034595 / HL / NHLBI NIH HHS / United States
P01 CA117969 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
R01 CA49449 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
HL 34595 / HL / NHLBI NIH HHS / United States
HHSN268201100003C / / PHS HHS / United States
R01 CA124908 / CA / NCI NIH HHS / United States
CA 40360 / CA / NCI NIH HHS / United States
1UM1 CA167552 / CA / NCI NIH HHS / United States
HHSN268201100004C / / PHS HHS / United States
CA 34944 / CA / NCI NIH HHS / United States
P01 CA87969 / CA / NCI NIH HHS / United States
R01 HL034594 / HL / NHLBI NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
P01 CA55075 / CA / NCI NIH HHS / United States
R01 HL026490 / HL / NHLBI NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
K07 CA140790 / CA / NCI NIH HHS / United States
HHSN268201100046C / / PHS HHS / United States
R01 CA049449 / CA / NCI NIH HHS / United States
R01 CA040360 / CA / NCI NIH HHS / United States
P01-CA117969 / CA / NCI NIH HHS / United States
HHSN268201100002C / / PHS HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
R01 CA097193 / CA / NCI NIH HHS / United States
R01 CA034944 / CA / NCI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States