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

Oncotarget. 2015 Feb 28;6(6):4516-26. doi: 10.18632/oncotarget.2799.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alkyl and Aryl Transferases / analysis
  • Alkyl and Aryl Transferases / biosynthesis*
  • Biomarkers, Tumor / analysis*
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / pathology*
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology*
  • Prognosis
  • Proportional Hazards Models

Substances

  • Biomarkers, Tumor
  • Alkyl and Aryl Transferases
  • geranylpyrophosphate olivetolate geranyltransferase