Expression of Genomic Instability-Related Molecules: Cyclin F, RRM2 and SPDL1 and Their Prognostic Significance in Pancreatic Adenocarcinoma.

Abstract

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the worst prognostic cancers, for which clinically valuable prognostic factors and individualized biomarker-driven cancer therapies are still lacking. Recent studies have shed some light on the crucial relationship between genomic instability and PDAC progression, which can be harnessed for the cancer diagnosis, prognosis, and personalized treatment. We therefore tested the hypothesis that differences in the expression of cyclin F, RRM2, and SPLD1, i.e., proteins being implicated in maintaining genomic stability, could account for differences in clinical outcome among PDAC patients. Here, we have shown for the first time that overexpression of SPDL1 protein is a potent independent prognostic factor associated with a better survival of PDAC patients. In turn, CCNF, RRM2, and SPDL1 mRNAs are independent prognostic markers for a poor survival, both by themselves and even more in combination with each other. These biomarkers may have a potential clinical utility in the management of this deadly disease. In the present study, we aimed to assess the selected components of cell cycle machinery, checkpoint, DNA repair, and synthesis, namely RRM2, cyclin F, and SPDL1 in pancreatic adenocarcinomas (PAC) by in-house immunohistochemistry (IHC) and bioinformatic analysis of public datasets, in terms of expression, correlation with clinicopathological parameters, and patient survival. Sixty eight patients with pancreatic ductal adenocarcinoma (PDAC) were included in our cohort study, and IHC was performed on tissue macroarrays. RNA-Seq-based transcriptome data for 177 PACs were retrieved from the Cancer Genome Atlas (TCGA). We found cyclin F, RRM2, and SPDL1 to be overexpressed at both protein and mRNA levels in tumor tissues compared to respective controls. Based on TCGA dataset, we have demonstrated that CCNF, RRM2, and SPDL1 are potent independent prognostic markers for poor overall survival, both by themselves and even more in combination with each other. Furthermore, high CCNF mRNA expression was associated with features of cancer progression. By contrast, overexpression of cyclin F or SPDL1 proteins denoted a good prognosis in PDAC patients; however, in the case of the former protein, the results did not reach statistical significance. Specifically, high levels of SPDL1 protein emerged as the most powerful independent prognostic factor associated with a better outcome. If validated, the CCNF/RRM2/SPDL1 three-gene panel developed in this study, as well as SPDL1 protein, may provide significant clinical implications for the prognosis prediction of PAC patients.