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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 months1. PDAC has been linked with obesity and glucose intolerance2,3,4, 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.

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Figure 1: Plasma metabolites and risk of future pancreatic cancer diagnosis.
Figure 2: Plasma BCAA levels are elevated during subclinical disease.
Figure 3: BCAA elevations are derived from a long-term pool of amino acids.

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Acknowledgements

We would like to acknowledge A. Deik and K. Bullock of the Broad Institute for assistance with LC-MS sample analyses and the Tang Histology facility in the Koch Institute Swanson Biotechnology Center for assistance processing mouse tissues. Cambridge Isotope Laboratories supplied 13C-BCAA diets for mouse labeling studies. We would like to thank C. Newgard and A. Goldberg for their thoughtful discussions regarding this manuscript. We would also like to thank the participants and staff of the Health Professionals Follow-Up Study (HPFS), Nurses' Health Study (NHS), Physicians' Health Study I (PHS) and Women's Health Initiative-Observational Study (WHI-OS) for their contributions as well as the cancer registries of the following states for their help: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Indiana, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington and Wyoming. NHS and HPFS are supported by US National Institutes of Health (NIH) grants P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, R01 CA49449 and 1UM1 CA167552. PHS is supported by NIH grants CA 97193, CA 34944, CA 40360, HL 26490 and HL 34595. The WHI program is funded by the NIH through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. We acknowledge additional support from grant F30 CA183474 to J.R.M.; from a Nestle Research Center award to the Broad Institute; from R01 DK081572 grant to T.J.W. and R.E.G.; from the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research and Pappas Family Research Fund for Pancreatic Cancer to C.S.F.; from the Burroughs Wellcome Fund, Damon Runyon Cancer Research Foundation, the Smith Family and the Stern Family to M.G.V.H.; and from NIH/NCI grant K07 CA140790, the American Society of Clinical Oncology Conquer Cancer Foundation, the Howard Hughes Medical Institute and Promises for Purple to B.M.W. M.G.V.H. additionally acknowledges support from P30-CA14051 and P01-CA117969, and major support for this project was provided by the Howard Hughes Medical Institute to B.M.W. and the Lustgarten Foundation to C.S.F., M.G.V.H. and B.M.W.

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All authors participated in the analysis and interpretation of data. C.W., C.B.C., P.K., C.Y., Y.B., M.K.T. and B.M.W. performed the statistical analyses of the human data. C.B.C., M.K.T., S.S.T., T.J.W., R.E.G. and B.M.W. evaluated the platform for analysis of plasma metabolites in large cohort studies. C.B.C., J.R.M., A.S. and K.P. performed metabolite profiling experiments. P.K., Y.B., M.K.T., S.S.T., S.O., M.J.S., E.L.G., Z.R.Q., D.A.R., J.M., H.D.S., J.M.G., B.B.C., S.L., J.W.-W., J.E.M., M.N.P. and C.S.F. assisted in data acquisition, management and interpretation from the four cohort studies. J.R.M. and M.E.T. conducted all mouse experiments with assistance from B.P.F., S.M.D., T.P., A.Y., T.L.D. and A.C.K. C.W., C.B.C., J.R.M., C.S.F., M.G.V.H. and B.M.W. designed the study and drafted the manuscript with input from all authors.

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Correspondence to Matthew G Vander Heiden or Brian M Wolpin.

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Mayers, J., Wu, C., Clish, C. et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 20, 1193–1198 (2014). https://doi.org/10.1038/nm.3686

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