Jared R. Mayers 1 , Chen Wu 2 , 3 , 4 , Clary B. Clish 5 , Peter Kraft 4 , 6 , Margaret E. Torrence 1 , Brian P. Fiske 1 , Chen Yuan 3 , Ying Bao 7 , Mary K. Townsend 7 , Shelley S. Tworoger 4 , 7 , Shawn M. Davidson 1 , Thales Papagiannakopoulos 1 , Annan Yang 8 , Talya L. Dayton 1 , Shuji Ogino 3 , 4 , 9 , Meir J. Stampfer 4 , 7 , 10 , Edward L. Giovannucci 4 , 7 , 10 , Zhi Rong Qian 3 , Douglas A. Rubinson 3 , Jing Ma 4 , 7 , Howard D. Sesso 4 , 11 , John Michael Gaziano 11 , 12 , Barbara B. Cochrane 13 , Simin Liu 14 , Jean Wactawski–Wende 15 , JoAnn E. Manson 4 , 7 , 11 , Michael N. Pollak 16 , Alec C. Kimmelman 8 , Amanda Souza 5 , Kerry Pierce 5 , Thomas J. Wang 17 , Robert E. Gerszten 5 , 18 , Charles S. Fuchs 3 , 7 , Matthew G. Vander Heiden 1 , 3 , 5 , † , Brian M. Wolpin 3 , 19 , †
28 September 2014
Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months 1 . PDAC has been linked with obesity and glucose intolerance 2- 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 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 2–fold 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 prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, 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.