GOT1/AST1 expression status as a prognostic biomarker in pancreatic ductal adenocarcinoma

// Fenja M Feld 1 , Philipp D Nagel 1 , Stephanie E Weissinger 1 , Claudia Welke 2 , Albrecht Stenzinger 3 , Peter Moller 1 , Jochen K Lennerz 1 1 Institute of Pathology, University Ulm 89081, Germany 2 Comprehensive Cancer Center Ulm, University Hospital Ulm 89081, Germany 3 University Hospital Heidelberg, Department of Pathology, University Heidelberg 69120, Germany Correspondence to: Jochen K. Lennerz, e-mail: jochen.lennerz@uni-ulm.de Keywords: pancreatic cancer, glutamic oxaloacetatic transaminase 1, KRAS , PDAC, biomarker Received: October 14, 2014      Accepted: November 20, 2014      Published: February 19, 2015 ABSTRACT Prognostication in pancreatic ductal adenocarcinoma (PDAC) remains a challenge. Recently, a link between mutated KRAS and glutamic-oxaloacetic transaminase (GOT1/AST1) has been described as part of the metabolic reprogramming in PDAC. The clinical relevance of this novel metabolic KRAS -GOT1 link has not been determined in primary human patient samples. Here we studied the GOT1 expression status as a prognostic biomarker in PDAC. We employed three independent PDAC cohorts with clinicopathological- and follow-up data: a) ICGC, comprising 57 patients with whole-exome sequencing and genome-wide expression profiling; b) ULM, composed of 122 surgically-treated patients with tissue-samples and KRAS status; c) a validation cohort of 140 primary diagnostic biopsy samples. GOT1 expression was assessed by RNA level (ICGC) or immunolabeling (ULM/validation cohort). GOT1 expression varied (ICGC) and correlation with the KRAS mutation- and expression status was imperfect ( P = 0.2, ICGC; P = 0.8, ULM). Clinicopathological characteristics did not differ when patients were separated based on GOT1 high vs. low ( P = 0.08–1.0); however, overall survival was longer in patients with GOT1-expressing tumors ( P = 0.093, ICGC; P = 0.049, ULM). Multivariate analysis confirmed GOT1 as an independent prognostic marker ( P = 0.009). Assessment in univariate ( P = 0.002) and multivariate models in the validation cohort ( P = 0.019), containing 66% stage IV patients, confirmed the independency of GOT1. We propose the GOT1 expression status as a simple and reliable prognostic biomarker in pancreatic ductal adenocarcinoma.