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

Fenja M Feld,Claudia Welke,Peter Möller,Albrecht Stenzinger,Jochen K Lennerz,Stephanie E Weissinger,Philipp D Nagel

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.

Highlights

Mortality rates in pancreatic ductal adenocarcinoma (PDAC) have not changed in decades and it remains the fourth leading cause of cancer related deaths [1, 2], with an overall 5-year survival rate of < 5% [1, 3] and a median overall survival time of 3–12 months [3,4,5]
Since the clinical relevance of the recently described KRAS-glutamic-oxaloacetic transaminase 1 (GOT1) link [21] is currently unknown in primary human patient samples, we examined the freely available International Cancer Genome Consortium (ICGC)-PDAC dataset
After confirming the robustness of GOT1 immunolabeling as a diagnostic assay in biopsy samples (Supplemental Figure 7), we propose GOT1 as a simple, efficient and reliable, independent prognostic biomarker in PDAC

Summary

Introduction

Mortality rates in pancreatic ductal adenocarcinoma (PDAC) have not changed in decades and it remains the fourth leading cause of cancer related deaths [1, 2], with an overall 5-year survival rate of < 5% [1, 3] and a median overall survival time of 3–12 months [3,4,5]. Pancreatic cancer cells derive their energy www.impactjournals.com/oncotarget in large parts from glutamine, which serves as an indirect substrate for the Krebs cycle and renders the cancer cell dependent on glutamine [21, 22]. This glutamine addiction [23] is striking because glutamine is a nonessential amino acid that can be synthesized from glucose [22]. Thereby, one hallmark mutation of pancreatic carcinoma, KRAS, mediates a shift in the cancer cell’s glutamine-based energy supply system towards other pathways. The clinical relevance of this novel metabolic KRAS-GOT1 link has not been determined in primary human patient samples

Methods

Results

Conclusion