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

Jared R. Mayers, Chen Wu, Clary B. Clish, Peter Kraft, Margaret E. Torrence, Brian P. Fiske, Chen Yuan, Ying Bao, Mary K. Townsend, Shelley S. Tworoger, Shawn M. Davidson, Thales Papagiannakopoulos, Annan Yang, Talya L. Dayton, Shuji Ogino, Meir J. Stampfer, Edward L. Giovannucci, Zhi Rong Qian, Douglas A. Rubinson, Jing MaHoward D. Sesso, John M. Gaziano, Barbara B. Cochrane, Simin Liu, Jean Wactawski-Wende, Joann E. Manson, Michael N. Pollak, Alec C. Kimmelman, Amanda Souza, Kerry Pierce, Thomas J. Wang, Robert E. Gerszten, Charles S. Fuchs, Matthew G. Vander Heiden, Brian M. Wolpin

Research output: Contribution to journalArticle

247 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1193-1198
Number of pages6
JournalNature medicine
Volume20
Issue number10
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mayers, J. R., Wu, C., Clish, C. B., Kraft, P., Torrence, M. E., Fiske, B. P., Yuan, C., Bao, Y., Townsend, M. K., Tworoger, S. S., Davidson, S. M., Papagiannakopoulos, T., Yang, A., Dayton, T. L., Ogino, S., Stampfer, M. J., Giovannucci, E. L., Qian, Z. R., Rubinson, D. A., ... Wolpin, B. M. (2014). Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nature medicine, 20(10), 1193-1198. https://doi.org/10.1038/nm.3686