title: GOT1/AST1 expression status as a prognostic biomarker in pancreatic ductal adenocarcinoma.
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.
authors.affiliation: Institute of Pathology, University Ulm 89081, Germany.
authors.forename: Fenja M
authors.initials: FM
authors.lastname: Feld
authors.affiliation: Institute of Pathology, University Ulm 89081, Germany.
authors.forename: Philipp D
authors.initials: PD
authors.lastname: Nagel
authors.affiliation: Institute of Pathology, University Ulm 89081, Germany.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Weissinger
authors.affiliation: Comprehensive Cancer Center Ulm, University Hospital Ulm 89081, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Welke
authors.affiliation: University Hospital Heidelberg, Department of Pathology, University Heidelberg 69120, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Institute of Pathology, University Ulm 89081, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.affiliation: Institute of Pathology, University Ulm 89081, Germany.
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019883:Alkyl and Aryl Transferases / Q000032:analysis / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D021441:Carcinoma, Pancreatic Ductal / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor; D019883:Alkyl and Aryl Transferases; C112459:geranylpyrophosphate olivetolate geranyltransferase