Abstract
Although the overall five-year survival of patients with pancreatic ductal adenocarcinoma (PDAC) is dismal, there are survival differences between cases with clinically and pathologically indistinguishable characteristics, suggesting that there are uncharacterized properties that drive tumor progression. Recent mRNA sequencing studies reported gene-expression signatures that define PDAC molecular subtypes that correlate with differences in survival. We previously identified Keratin 17 (K17) as a negative prognostic biomarker in other cancer types. Here, we set out to determine if K17 is as accurate as molecular subtyping of PDAC to identify patients with the shortest survival. K17 mRNA was analyzed in two independent PDAC cohorts for discovery (n = 124) and validation (n = 145). Immunohistochemical localization and scoring of K17 immunohistochemistry (IHC) was performed in a third independent cohort (n = 74). Kaplan-Meier and Cox proportional-hazard regression models were analyzed to determine cancer specific survival differences in low vs. high mRNA K17 expressing cases. We established that K17 expression in PDACs defines the most aggressive form of the disease. By using Cox proportional hazard ratio, we found that increased expression of K17 at the IHC level is also associated with decreased survival of PDAC patients. Additionally, within PDACs of advanced stage and negative surgical margins, K17 at both mRNA and IHC level is sufficient to identify the subgroup with the shortest survival. These results identify K17 as a novel negative prognostic biomarker that could inform patient management decisions.
Highlights
Available biomarkers that guide the management of pancreatic ductal adenocarcinoma (PDAC) have limited ability to predict patient clinical course or survival and prior large-scale genomic studies demonstrated that common driver mutations or other mutations lack prognostic value[4,5,6,7]
To define a threshold that provided maximal stratification of survival differences based on keratin 17 (K17) mRNA, the maximum likelihood fit of a Cox proportional hazard model was used. 76% of the cases were classified as low K17 while 24% of cases were classified as high K17 (Fig. 1a)
To determine survival differences between low and high K17 cases, we performed a Kaplan- Meier (K-M) and Cox proportional-hazard regression model of survival and found that patients with high K17 PDACs had a median survival of 13 months, which was shorter than for patients with low K17 PDACs, who had a median survival of 18 months (HR = 1.6, p = 0.0450, CI = 0.935–2.723) (Fig. 1b)
Summary
Available biomarkers that guide the management of PDAC have limited ability to predict patient clinical course or survival and prior large-scale genomic studies demonstrated that common driver mutations or other mutations lack prognostic value[4,5,6,7]. Recent RNA sequencing (RNA-Seq) studies[20,21], including ours[22], reported that mRNA expression defines molecular subtypes of PDAC including the relatively less aggressive “classical” subtype and the more aggressive “basal-like” subtype that is defined based on the expression of a 25-gene expression signature[20,22]. Embedded within this gene-expression signature, we identified the presence of K17 mRNA. Two different and unbiased approaches, biomarker-based discovery by proteomics and molecular subtyping by RNA-Seq, point to the importance of K17 in PDAC
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