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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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Validation of GOT1 expression status as an independent prognostic biomarker in pancreatic ductal adenocarcinoma(a) Kaplan–Meier estimates of outcome for GOT1 positive vs. negative samples in our validation cohort. (b, c). Forest plots of log hazard ratios (HR) from univariate (b) and multivariate (c) Cox proportional regression models for overall survival according to baseline clinical characteristics. Note, for comparison of effect size among characteristics associated with shorter overall survival, we plotted GOT1-negativity (GOT1 neg.). (d, e) Stacked cumulative incidence of death in the validation cohort, plotted over our prediction model that was built based on survival data in our screening cohort (Figure. 2). Note, the shift between validation- and prediction curves (d) is due to the inclusion of 93 patients with biopsy-confirmed metastatic PDAC; curves shift when comparison is restricted to patients in stage I–III(e).Abbreviations: mo., months; HR, hazard ratio; CI, confidence interval.
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Figure 3: Validation of GOT1 expression status as an independent prognostic biomarker in pancreatic ductal adenocarcinoma(a) Kaplan–Meier estimates of outcome for GOT1 positive vs. negative samples in our validation cohort. (b, c). Forest plots of log hazard ratios (HR) from univariate (b) and multivariate (c) Cox proportional regression models for overall survival according to baseline clinical characteristics. Note, for comparison of effect size among characteristics associated with shorter overall survival, we plotted GOT1-negativity (GOT1 neg.). (d, e) Stacked cumulative incidence of death in the validation cohort, plotted over our prediction model that was built based on survival data in our screening cohort (Figure. 2). Note, the shift between validation- and prediction curves (d) is due to the inclusion of 93 patients with biopsy-confirmed metastatic PDAC; curves shift when comparison is restricted to patients in stage I–III(e).Abbreviations: mo., months; HR, hazard ratio; CI, confidence interval.

Mentions: As a next necessary step, a prognostic biomarker candidate has to be validated in an independent patient cohort and we employed a separate PDAC cohort consisting of 140 consecutive biopsy samples; reflecting the typical clinical scenario, i.e., including ~63% (n = 81/140) of patients with stage IV disease at time of presentation (Table 3). In these 140 patient samples, we determined the GOT1 status by immunolabling (n = 73 GOT1+ vs. n = 67 GOT1–) and found significantly longer survival in the GOT1 positive group (14.5 vs. 7.7 months; P = 0.0012; Figure 3a). The striking difference of over 6 months median OS was accompanied by a trend towards lower grade tumors in the GOT1-positive subgroup and a higher rate of metastasis in the GOT1-negative subgroup (Table 3). To assess the relative effect of these factors, we performed uni- and multivariate testing and validated that GOT1 is independent from these factors and actually outperformed other prognostically relevant factors in this cohort (Figure 3b/c).


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)

Validation of GOT1 expression status as an independent prognostic biomarker in pancreatic ductal adenocarcinoma(a) Kaplan–Meier estimates of outcome for GOT1 positive vs. negative samples in our validation cohort. (b, c). Forest plots of log hazard ratios (HR) from univariate (b) and multivariate (c) Cox proportional regression models for overall survival according to baseline clinical characteristics. Note, for comparison of effect size among characteristics associated with shorter overall survival, we plotted GOT1-negativity (GOT1 neg.). (d, e) Stacked cumulative incidence of death in the validation cohort, plotted over our prediction model that was built based on survival data in our screening cohort (Figure. 2). Note, the shift between validation- and prediction curves (d) is due to the inclusion of 93 patients with biopsy-confirmed metastatic PDAC; curves shift when comparison is restricted to patients in stage I–III(e).Abbreviations: mo., months; HR, hazard ratio; CI, confidence interval.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414208&req=5

Figure 3: Validation of GOT1 expression status as an independent prognostic biomarker in pancreatic ductal adenocarcinoma(a) Kaplan–Meier estimates of outcome for GOT1 positive vs. negative samples in our validation cohort. (b, c). Forest plots of log hazard ratios (HR) from univariate (b) and multivariate (c) Cox proportional regression models for overall survival according to baseline clinical characteristics. Note, for comparison of effect size among characteristics associated with shorter overall survival, we plotted GOT1-negativity (GOT1 neg.). (d, e) Stacked cumulative incidence of death in the validation cohort, plotted over our prediction model that was built based on survival data in our screening cohort (Figure. 2). Note, the shift between validation- and prediction curves (d) is due to the inclusion of 93 patients with biopsy-confirmed metastatic PDAC; curves shift when comparison is restricted to patients in stage I–III(e).Abbreviations: mo., months; HR, hazard ratio; CI, confidence interval.
Mentions: As a next necessary step, a prognostic biomarker candidate has to be validated in an independent patient cohort and we employed a separate PDAC cohort consisting of 140 consecutive biopsy samples; reflecting the typical clinical scenario, i.e., including ~63% (n = 81/140) of patients with stage IV disease at time of presentation (Table 3). In these 140 patient samples, we determined the GOT1 status by immunolabling (n = 73 GOT1+ vs. n = 67 GOT1–) and found significantly longer survival in the GOT1 positive group (14.5 vs. 7.7 months; P = 0.0012; Figure 3a). The striking difference of over 6 months median OS was accompanied by a trend towards lower grade tumors in the GOT1-positive subgroup and a higher rate of metastasis in the GOT1-negative subgroup (Table 3). To assess the relative effect of these factors, we performed uni- and multivariate testing and validated that GOT1 is independent from these factors and actually outperformed other prognostically relevant factors in this cohort (Figure 3b/c).

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