Abstract
BackgroundDespite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. We analyzed the expression levels of CNKSR1, a scaffold that influences MAPK/ERK pathway activity, in clinical pancreas cancer specimens and their impact on survival of patients with pancreatic cancer.MethodsImmunohistochemical staining for CNKSR1 expression was performed on 120 specimens from three independent pancreatic cancer tissue registries, phospho-ERK levels were measured in 86 samples. Expression was divided into CNKSR1 low and CNKSR1 high and correlated with clinicopathological variables including overall survival using multivariate Cox proportional hazard ratio models.ResultsCNKSR1 expression was increased in tumors compared to matched normal uninvolved resection specimens (p = 0.004). 28.3% (34/120) of patient specimens stained as CNKSR1 low compared to 71.7% (86/120) of specimens which stained as CNKSR1 high. High CNKSR1 expression was more prevalent in low grade tumors (p = 0.04). In multivariate analysis, low CNKSR1 expression status was independently correlated with decreased overall survival (HR = 2.146; 95% CI 1.34 to 3.43). When stratifying primary, non-metastatic tumor biopsies by CNKSR1 expression, resection was associated with improved survival in patients with high CNKSR1 expression (p < 0.0001) but not low CNKSR1 expression (p = 0.3666). Pancreatic tumors with nuclear in addition to cytoplasmic CNKSR1 staining (32/107) showed increased nuclear phospho-ERK expression compared to tumor with cytoplasmic CNKSR1 staining only (p = 0.017).ConclusionCNKSR1 expression is increased in pancreatic tissue specimens and was found to be an independent prognostic marker of overall survival. CNKSR1 may help to identify patient subgroups with unfavorable tumor biology in order to improve risk stratification and treatment selection. Cellular distribution of CNKSR1 was correlated with nuclear pERK expression.
Highlights
Despite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/extracellular-signalregulated kinase (ERK) pathway activation states, and clinical outcome in this disease
CNKSR1 expression levels are heterogeneous in pancreatic adenocarcinoma Combining cases from all three cohorts, 6 cases showed no expression (5.0%), 28 cases were scored as 1+ (23.3%), Fig. 2 Photomicrographs of pancreatic cancer tissue microarray (TMA) cores of high CNKSR1 immunohistochemical staining: a, b positive for CNKSR1; c, d strongly positive for CNKSR1
To validate the expression pattern used for the clinical outcome associations in an independent cohort, 71 cases from a commercially available pancreatic cancer TMA and 47 cases from a TMA constructed at an outside institution were subject to the same CNKSR1 staining and reviewed by the same study pathologists (MM, MA)
Summary
Despite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. While advances in the understanding of cancer biology, screening and risk-reducing interventions, and improved treatments have significantly reduced cancer mortality overall, pancreatic cancer remains a deadly disease. Even in the minority of patients who are able to undergo surgical resection, median overall survival remains poor [3]. Considering the variability of clinical outcome and the uncertainty of the role of surgical resection in cancers at high risk for early progression, prognostic biomarkers accurately stratifying patients for individualized clinical decision-making would fill an unmet clinical need
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