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

Feld FM, Nagel PD, Weissinger SE, Welke C, Stenzinger A, Möller P, Lennerz JK - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University Ulm 89081, Germany.

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.

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Overview of the recently described KRAS function in pancreatic ductal adenocarcinoma and findings in screening cohorts(a) Mutant KRAS increases redox-equivalents at cost of energy. Reprogramming includes the induction of GOT1, which is essential for pancreatic cancer cell survival; modeled after Son et al., 2013. (b)Findings in the ICGC cohort. Panel allows comparison of sample-specific mutations (as determined by whole-exome sequencing; upper histogram), KRAS mutation status and enzyme expression levels (upper heatmap), relative fraction of mutations (column graphs), and key clinicopathological features of samples at the case-level (columns). There is no correlation between KRAS mutations and GOT1 expression level (details see results). (c)Immunohistochemical staining pattern of GOT1 in a positive (left) and a negative case (right). Positivity is defined as cytoplasmic GOT1 immunoreactivity (red) that is more intense than the stroma (arrow). Note, liver cells show immunoreactivity and act as an internal staining control. (d)Findings in the ULM cohort. Panel compares KRAS mutation status (by pyrosequencing), GOT1 protein expression, proliferation ratio (Ki-67), and key clinicopathological features at the case-level (columns). There is also no correlation between KRAS mutation status and GOT1 protein expression.Abbreviations: GOT1, glutamic oxaloacetic transaminase 1; GLUD1, glutamate dehydrogenase 1; MDH1, malate dehydrogenase1; ME1, malic enzyme 1.
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Figure 1: Overview of the recently described KRAS function in pancreatic ductal adenocarcinoma and findings in screening cohorts(a) Mutant KRAS increases redox-equivalents at cost of energy. Reprogramming includes the induction of GOT1, which is essential for pancreatic cancer cell survival; modeled after Son et al., 2013. (b)Findings in the ICGC cohort. Panel allows comparison of sample-specific mutations (as determined by whole-exome sequencing; upper histogram), KRAS mutation status and enzyme expression levels (upper heatmap), relative fraction of mutations (column graphs), and key clinicopathological features of samples at the case-level (columns). There is no correlation between KRAS mutations and GOT1 expression level (details see results). (c)Immunohistochemical staining pattern of GOT1 in a positive (left) and a negative case (right). Positivity is defined as cytoplasmic GOT1 immunoreactivity (red) that is more intense than the stroma (arrow). Note, liver cells show immunoreactivity and act as an internal staining control. (d)Findings in the ULM cohort. Panel compares KRAS mutation status (by pyrosequencing), GOT1 protein expression, proliferation ratio (Ki-67), and key clinicopathological features at the case-level (columns). There is also no correlation between KRAS mutation status and GOT1 protein expression.Abbreviations: GOT1, glutamic oxaloacetic transaminase 1; GLUD1, glutamate dehydrogenase 1; MDH1, malate dehydrogenase1; ME1, malic enzyme 1.

Mentions: Recently, a novel metabolic function of the highly prevalent KRAS mutation in PDAC has been identified [21]. Briefly, pancreatic cancer cells derive their energy 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]. Son et al., have now shown that the KRAS mutation modulates the associated metabolic pathways by inducing GOT1 (in short, KRAS-GOT1 link) [21, 24]. The resulting upregulation shifts glutamine towards enzymes that orchestrate cell growth and the redox maintenance system (Figure 1a). Thereby, one hallmark mutation of pancreatic carcinoma, KRAS, mediates a shift in the cancer cell's glutamine-based energy supply system towards other pathways. Currently, the clinical relevance of this novel metabolic KRAS-GOT1 link has not been determined in primary human patient samples.


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

Feld FM, Nagel PD, Weissinger SE, Welke C, Stenzinger A, Möller P, Lennerz JK - Oncotarget (2015)

Overview of the recently described KRAS function in pancreatic ductal adenocarcinoma and findings in screening cohorts(a) Mutant KRAS increases redox-equivalents at cost of energy. Reprogramming includes the induction of GOT1, which is essential for pancreatic cancer cell survival; modeled after Son et al., 2013. (b)Findings in the ICGC cohort. Panel allows comparison of sample-specific mutations (as determined by whole-exome sequencing; upper histogram), KRAS mutation status and enzyme expression levels (upper heatmap), relative fraction of mutations (column graphs), and key clinicopathological features of samples at the case-level (columns). There is no correlation between KRAS mutations and GOT1 expression level (details see results). (c)Immunohistochemical staining pattern of GOT1 in a positive (left) and a negative case (right). Positivity is defined as cytoplasmic GOT1 immunoreactivity (red) that is more intense than the stroma (arrow). Note, liver cells show immunoreactivity and act as an internal staining control. (d)Findings in the ULM cohort. Panel compares KRAS mutation status (by pyrosequencing), GOT1 protein expression, proliferation ratio (Ki-67), and key clinicopathological features at the case-level (columns). There is also no correlation between KRAS mutation status and GOT1 protein expression.Abbreviations: GOT1, glutamic oxaloacetic transaminase 1; GLUD1, glutamate dehydrogenase 1; MDH1, malate dehydrogenase1; ME1, malic enzyme 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Overview of the recently described KRAS function in pancreatic ductal adenocarcinoma and findings in screening cohorts(a) Mutant KRAS increases redox-equivalents at cost of energy. Reprogramming includes the induction of GOT1, which is essential for pancreatic cancer cell survival; modeled after Son et al., 2013. (b)Findings in the ICGC cohort. Panel allows comparison of sample-specific mutations (as determined by whole-exome sequencing; upper histogram), KRAS mutation status and enzyme expression levels (upper heatmap), relative fraction of mutations (column graphs), and key clinicopathological features of samples at the case-level (columns). There is no correlation between KRAS mutations and GOT1 expression level (details see results). (c)Immunohistochemical staining pattern of GOT1 in a positive (left) and a negative case (right). Positivity is defined as cytoplasmic GOT1 immunoreactivity (red) that is more intense than the stroma (arrow). Note, liver cells show immunoreactivity and act as an internal staining control. (d)Findings in the ULM cohort. Panel compares KRAS mutation status (by pyrosequencing), GOT1 protein expression, proliferation ratio (Ki-67), and key clinicopathological features at the case-level (columns). There is also no correlation between KRAS mutation status and GOT1 protein expression.Abbreviations: GOT1, glutamic oxaloacetic transaminase 1; GLUD1, glutamate dehydrogenase 1; MDH1, malate dehydrogenase1; ME1, malic enzyme 1.
Mentions: Recently, a novel metabolic function of the highly prevalent KRAS mutation in PDAC has been identified [21]. Briefly, pancreatic cancer cells derive their energy 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]. Son et al., have now shown that the KRAS mutation modulates the associated metabolic pathways by inducing GOT1 (in short, KRAS-GOT1 link) [21, 24]. The resulting upregulation shifts glutamine towards enzymes that orchestrate cell growth and the redox maintenance system (Figure 1a). Thereby, one hallmark mutation of pancreatic carcinoma, KRAS, mediates a shift in the cancer cell's glutamine-based energy supply system towards other pathways. Currently, the clinical relevance of this novel metabolic KRAS-GOT1 link has not been determined in primary human patient samples.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University Ulm 89081, Germany.

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.

Show MeSH
Related in: MedlinePlus