Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease, in part because of the lack of molecular biomarkers, allowing the rationale assignment of patient subgroups to appropriate targeted therapies. As a result, almost all PDAC patients are treated with one of two chemotherapeutic regimens (Gem/Abraxane or FOLFIRINOX), with marginal improvement in overall survival. In the last two years, RNA sequencing (RNASeq) studies reported that mRNA expression from bulk tumor defines molecular subtypes of PDAC that are highly correlated with survival. The 25‐gene mRNA signature defining the clinically most aggressive subtype of PDAC has yielded a refined landscape through which biomarker and targetable therapeutics can be identified. Thus, the aim of the current study was to determine if K17, one member of this mRNA signature, is sufficient to define the most aggressive subtype of PDAC and to validate K17 by immunohistochemistry (IHC) as a negative prognostic biomarker.Methods and ResultsData‐mining of 125 cases from the University of North Carolina Medical Center (Moffitt et al., 2015) identified K17 mRNA as an independent and sufficient biomarker of the most aggressive molecular subtype of PDAC (hazard ratio [HR] for death at 6 years =1.676, p=0.012). K17 mRNA was next validated as a negative prognostic biomarker in The Cancer Genome Atlas (TCGA) database of margin‐positive (n=48, HR=2.726, p=0.005), and lymph node‐positive (n=107 HR=1.913, p=0.016) PDAC. Increased K17 mRNA was also correlated with protein expression by qRT‐PCR and Immunohistochemistry (IHC) in formalin‐fixed paraffin‐embedded tissue blocks. IHC stained demonstrated specific staining in malignant and pre‐malignant cells. Tumors were classified as high for K17 based on the proportion of cells that showed strong (2+) staining in ≥ 25% of tumor cells. K17 was validated as a powerful independent prognostic biomarker in an separate set of PDACs from Stony Brook Medicine, Memorial Sloan Kettering Cancer Center and the University of Massachusetts Memorial Medical Center (n=82, HR=2.444, p=0.002). High‐K17 cases had shorter survival among cases with positive regional lymph nodes metastasis (n=52, HR=2.542, p=0.006) and negative regional lymph nodes metastasis (n=30, HR= 2.883, p=0.058).ConclusionThis is the first study to show that the expression of a single gene, K17, can accurately define the most aggressive PDAC subtype and is an independent, clinically relevant, prognostic biomarker. K17 expression, measured at the protein level by IHC, performs better than mRNA testing to predict outcome at the time of initial diagnosis and has the potential to inform clinical decisions regarding chemotherapeutic intervention.Support or Funding InformationThe Marvin Kuschner AccountThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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