Prognostic Marker In Pancreatic Ductal Adenocarcinoma Research Articles

Methylation of FAM110C is a synthetic lethal marker for ATR/CHK1 inhibitors in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. An epigenetic-based synthetic lethal strategy provides a novel opportunity for PDAC treatment. Finding more DNA damage repair (DDR)-related or cell fate-related molecules with aberrant epigenetic changes is becoming very important. Family with sequence similarity 110C (FAM110C) is a cell fate-related gene and its function in cancer remains unclear. Seven cell lines, 34 cases of intraductal papillary mucinous neoplasm (IPMN), 15 cases of mucinous cystic neoplasm (MCN) and 284 cases of PDAC samples were employed. Methylation-specific PCR, western blot, CRISPR knockout, immunoprecipitation and a xenograft mouse model were used in this study. FAM110C is methylated in 41.18% (14/34) of IPMN, 46.67% (7/15) of MCN and 72.89% (207/284) of PDAC, with a progression trend from IPMN/MCN to pancreatic cancer (P = 0.0001, P = 0.0389). FAM110C methylation is significantly associated with poor overall survival (OS) (P = 0.0065) and is an independent prognostic marker for poor OS (P = 0.0159). FAM110C inhibits PDAC cells growth both in vitro and in vivo, serving as a novel tumor suppressor. FAM110C activates ATM and NHEJ signaling pathways by interacting with HMGB1. Loss of FAM110C expression sensitizes PDAC cells to VE-822 (an ATR inhibitor) and MK-8776 (a CHK1 inhibitor). FAM110C methylation is a potential diagnostic and prognostic marker in PDAC, and its epigenetic silencing sensitizes PDAC cells to ATR/CHK1 inhibitors.

C-reactive protein is a prognostic biomarker in pancreatic ductal adenocarcinoma patients.

The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is approximately 11% and has only improved marginally over the last three decades. For operable PDAC, resection and adjuvant FOLFIRINOX chemotherapy is standard of care. There is growing interest in perioperative regimens to improve outcomes. The non-randomized Phase II study "Gemcitabine and Abraxane for resectable Pancreatic cancer" (GAP) demonstrated the feasibility of perioperative gemcitabine/abraxane. Long-term survival in PDAC requires an effective immune response; hence, we undertook this translational study of the GAP trial cohort to identify immune-oncology biomarkers for clinical use. We combined Nanostring nCounter technology with immunohistochemistry to investigate the correlation between gene expression and overall patient survival. Findings were investigated in samples from the International Cancer Genome Consortium (ICGC, n=88) and the Australian Pancreatic Genome Initiative (APGI, n=227). We confirmed that human equilibrative nucleoside transporter 1 (hENT1) expression was not a prognostic marker in PDAC but patients with high levels of hENT1 were more likely to live longer than 24 months post-surgery. Additionally, CD274 (PD-L1) and two novel biomarkers of survival, cathepsin W (CTSW) and C-reactive protein (CRP), were identified in the GAP cohort (n=19). CRP expression was confirmed in data from the ICGC. Although PD-L1 and CTSW proteins were not significant across all three cohorts, results show that low CRP mRNA and protein expression are associated with longer overall survival in all three patient groups. PDAC patients with long survival have higher hENT1 expression levels. Furthermore, CRP expression is a biomarker of poor prognosis following perioperative chemotherapy and resection in PDAC patients and thus may be useful for identifying patients who could benefit from more aggressive adjuvant strategies.

Hypoxia-Induced miR-210 Promotes Endothelial Cell Permeability and Angiogenesis via Exosomes in Pancreatic Ductal Adenocarcinoma.

Exosomes have been proven to play important diagnostic, regulatory, or communication roles in tumorigenesis, tumor progression, or metastasis; in recent studies, lots of molecules, including miRNAs, were found to be aberrantly expressed in tumor exosomes and were correlated with tumor development. However, studies about the expression, relationship, or control mechanisms of miRNAs in exosomes in pancreatic ductal adenocarcinoma (PDAC) are scarce and urgently needed. The aim of this article was to identify and investigate abnormally expressed miRNAs in PDAC exosomes in vivo and in vitro. Microarray studies were used to detect aberrantly expressed miRNAs in PDAC exosomes, and miR-210 expression in cells or exosomes was further analyzed by qRT-PCR. Bioinformatics analyses, dual-luciferase assays, WB, and other assays were utilized to explore the miRNA molecular mechanisms. The living cell coculture model and immunofluorescence analysis were employed to image the communication between PDAC cells and endothelial cells. Other biological experiments in the study include a real-time intravital imaging system, EdU, transwell, xenograft models, and so on. miR-210 is significantly expressed in PDAC exosomes and malignant cells. High miR-210 significantly facilitated tumor angiogenesis, cell invasion, and proliferation in PDAC cells. Further mechanistic detection revealed that miR-210 negatively regulated EFNA3 expression and participated in the PI3K/AKT/VEGFA or Wnt/Β-catenin/RHOA pathways, thus promoting tumor angiogenesis and cellular permeability. PDAC cells promote endothelial angiogenesis or permeability via miR-210 transmission by tumor exosomes. Exosomal miR-210 promotes PDAC progression in vivo. Further detection of PDAC plasma exosomal miR-210 suggests that exosomal miR-210 expression was high and significantly associated with vascular invasion and TNM stage and was an independent risk factor for PDAC overall survival. PDAC cell-secreted exosomes could promote angiogenesis and cellular permeability of neighboring endothelial angiogenesis or permeability via miR-210 transmission. Exosomal miR-210 may play important roles in tumor biology and may be a useful prognostic marker in PDAC.

Concurrent Overexpression of Two Hyaluronidases, KIAA1199 and TMEM2, Strongly Predicts Shorter Survival After Resection in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by accelerated hyaluronan metabolism. Our previous studies have shown increased expression of 2 newly identified hyaluronidases, KIAA1199 and transmembrane protein 2 (TMEM2), in PDAC. However, the relationship between these 2 hyaluronidases is unknown. In the present study, we investigated the correlation between KIAA1199 and TMEM2 expression in PDAC. Using quantitative real-time reverse transcription polymerase chain reaction, we analyzed KIAA1199 and TMEM2 mRNA expression in 11 PDAC cell lines and frozen tissues from 12 patients with PDAC. We used immunohistochemistry to investigate expression patterns of KIAA1199 and TMEM2 in archival tissues obtained from 92 patients with PDAC who underwent surgical resection. We compared survival between 4 groups according to expression patterns of KIAA1199 and TMEM2. We found a significantly positive correlation between KIAA1199 and TMEM2 mRNA in PDAC cell lines and tissues. Immunohistochemical analysis found that median overall survival was 30.2 months in patients with low expression of KIAA1199 and TMEM2 and 12.5 months in those with high expression of both. Patients with high expression of KIAA1199 and TMEM2 had significantly shorter survival than other patient groups. Concurrent overexpression of these 2 hyaluronidases could be a strong prognostic marker in PDAC.

Values of a novel pyroptosis-related genetic signature in predicting outcome and immune status of pancreatic ductal adenocarcinoma.

BackgroundPyroptosis is an emerging form of programmed cell death associated with progression in malignancies. Yet, there are few studies reporting on the association between pancreatic ductal adenocarcinoma (PDAC) and pyroptosis. Therefore, we aimed to construct a pyroptosis-related genetic signature to predict the clinical outcome and immune status in PDAC patients.MethodsRNA-seq data of 176 PDAC patients from The Cancer Genome Atlas (TCGA) and 167 PDAC patients from the Genotype-Tissue Expression Project were analysed for pyroptosis-related differentially expressed genes (DEGs) between PDAC and normal pancreas. The risk signature of DEGs was analysed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis and its accuracy was validated in the Gene Expression Omnibus (GEO) cohort (n = 190). Functional enrichment analyses were performed to explore the mechanisms of the DEGs. The immune characteristics were evaluated using single-sample gene set enrichment analysis and ESTIMATE algorithms for each group.ResultsA nine-gene risk signature was generated from LASSO Cox regression analysis and classified PDAC patients into either a high- or low-risk group according to the median risk score. The high-risk group had significantly shorter overall survival than the low-risk group and it was verified in the external GEO database. A nomogram based on the risk signature was constructed and showed an ideal prediction performance. Functional enrichment analyses revealed that pyroptosis might regulate the tumor immune microenvironment in PDAC. Immune infiltration evaluation suggested that immune status was more activated in the low-risk group than in the high-risk group.ConclusionThe risk signature encompassing nine pyroptosis-related genes may be a prognostic marker for PDAC. Pyroptosis might affect the prognosis of PDAC patients via regulating the tumor immune microenvironment.

Prognostic Value of COX-2, NF-κB, and Sp1 Tissue Expressions in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis.

Pancreatic ductal adenocarcinoma (PDAC) is deadly cancer with a poor prognosis. Molecular prognostic markers are needed to predict the patient's survival. The cyclooxygenase-2 enzyme (COX-2) and its 2 major transcription factors--nuclear factorkappa B (NF-κB) and specificity protein 1 (Sp1)--are activated during inflammation caused by neoplasia. Several studies have investigated the association between the COX-2, NF-κB, and Sp1 tissue expressions with the patient's overall survival. Therefore, we conducted this systematic review and meta-analysis to evaluate those studies. We searched for relevant articles from the MEDLINE database through June 2020. Studies were eligible if they included dichotomized tissue protein expression status and the overall survival as the outcome. We used RevMan and ProMeta programs to perform the meta-analysis. We identified 11 eligible studies. The meta-analysis showed that COX-2 tissue expression was associated with decreased overall survival (crude HR = 1.35; 95% CI, 1.05-1.74), although the result was not significant when controlling for other covariates. The NF-κB tissue expression was associated with decreased overall survival (crude HR = 2.18; 95% CI, 1.49-3.18), although it was not significant when controlling for other covariates. The Sp1 tissue expression showed significantly decreased overall survival even when adjusted with other covariates (aHR = 3.47; 95% CI, 1.52-7.94). The limitations included searching only for English publications and the substantial heterogeneity among the studies. COX-2, NF-κB, and Sp1 tissue expressions have the potential to be used as prognostic markers in PDAC. Further studies are still needed to clarify the associations.

How pancreatic adenocarcinoma might cause diabetes? The role of TGF- β

Pancreatic ductal adenocarcinoma (PDAC) is a deadly sickness that stays incurable due to past due diagnosis, which renders any healing intervention challenging. Most PDAC sufferers expand de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes continues to be unfolding. Using a mouse version of KrasG12D-pushed PDAC, which faithfully recapitulates the development of the human sickness, we determined a large and selective depletion of β-cells, taking place very early on the degrees of preneoplastic lesions. Mechanistically, it turned into observed that accelerated TGF beta (TGF-β) signaling throughout PDAC development induced erosion of β-mobileular mass thru apoptosis. Suppressing TGF-β signaling, both pharmacologically thru TGF-β immunoneutralization or genetically thru deletion of Smad4 or TGF-β kind II receptor (TβRII), afforded size able safety in opposition to PDAC-pushed β-mobileular depletion. From a translational perspective, each activation of TGF-β signaling and depletion of β-cells often arise in human PDAC, imparting a mechanistic cause of the pathogenesis of diabetes in PDAC sufferers, and similarly implicating new- onset diabetes as a capability early prognostic marker for PDAC. In this mini review we try to analyze the principle relationships between pancreatic cancer and diabetes and vice versa in addition to the implication of TGF-β signaling as a likely goal for attenuating diabetes in pancreatic most cancers patients.

CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer.

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, whose expression is upregulated in some types of malignant tumors. High levels of CD109 in tumor cells have been reported to correlate with poor prognosis; however, significance of CD109 stromal expression in human malignancy has not been elucidated. In this study, we investigated the tumorigenic properties of CD109 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis of 92 PDAC surgical specimens revealed that positive CD109 expression in tumor cells was significantly associated with poor prognosis (disease-free survival, p = 0.003; overall survival, p = 0.002), and was an independent prognostic factor (disease-free survival, p = 0.0173; overall survival, p = 0.0104) in PDAC. Furthermore, CD109 expression was detected in the stroma surrounding tumor cells, similar to that of α-smooth muscle actin, a histological marker of cancer-associated fibroblasts. The stromal CD109 expression significantly correlated with tumor progression in PDAC (TNM stage, p = 0.033; N factor, p = 0.024; lymphatic invasion, p = 0.028). In addition, combined assessment of CD109 in tumor cells and stroma could identify the better prognosis group of patients from the entire patient population. In MIA PaCa-2 PDAC cell line, we demonstrated the involvement of CD109 in tumor cell motility, but not in PANC-1. Taken together, CD109 not only in the tumor cells but also in the stroma is involved in the progression and prognosis of PDAC, and may serve as a useful prognostic marker in PDAC.

Prognostic significance of high mobility group A2 (HMGA2) in pancreatic ductal adenocarcinoma: malignant functions of cytoplasmic HMGA2 expression

PurposeHMGA2 has frequently been found in benign as well as malignant tumors and a significant association between HMGA2 overexpression and poor survival in different malignancies was described. In pancreatic ductal adenocarcinoma (PDAC), nuclear HMGA2 expression is associated with tumor dedifferentiation and presence of lymph node metastasis. Nevertheless, the impact of HMGA2 occurrence in other cell compartments is unknown.MethodsIntracellular distribution of HMGA2 was analyzed in PDAC (n = 106) and peritumoral, non-malignant ducts (n = 28) by immunohistochemistry. Findings were correlated with clinico-pathological data. Additionally, intracellular HMGA2 presence was studied by Western blotting of cytoplasmic and nuclear fractions of cultured cells.ResultsHMGA2 was found in the cytoplasm and in the nucleus of cultured cells. In human tumor tissue, HMGA2 was also frequently found in the cytoplasm and the nucleus of tumor cells, however, nuclear staining was generally stronger. Direct comparison from tumor tissue with corresponding non-neoplastic peritumoral tissue revealed significantly stronger expression in tumors (p = 0.003). Of note, the nuclear staining was significantly stronger in lymph node metastatic cell nuclei compared to primary tumor cell nuclei (p = 0.049). Interestingly, cytoplasmic staining positively correlated with lymph vessel (p = 0.004) and venous invasion (p = 0.046).ConclusionHMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.

Genomic relevance of FGF14 and associated genes on the prognosis of pancreatic cancer.

BackgroundFibroblast (FGFs) and insulin (IGF) growth factor pathways are among 10 most recurrently altered genomic pathways in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic and therapeutic relevance of FGF and IGF pathways in PDAC is largely unknown.MethodsWe investigated the relationship between fibroblast and insulin pathway gene expression and clinicopathological features in three independent transcriptomic cohorts of 532 PDAC patients. Furthermore, we have examined the coexpressed genes specific to the prognostic marker identified from these cohorts. Statistical tests including Fisher-exact\\Chi-square, Kaplan–Meier, Pearson Correlation and cox regression analyses were performed. Additionally, pathway analysis of gene-specific co-expressed genes was also performed.ResultsThe dysregulation of six genes including FGF9, FGF14, FGFR1, FGFR4, IGF2BP2 and IGF2BP3 were significantly associated with different clinical characteristics (including grade, stage, recurrence and nodes) in PDAC cohorts. 11 genes (including FGF9, FGF13, FGF14, FGF17, FGFR1, FGFRL1, FGFBP3, IGFBP3, IGF2BP2, IGF2BP3 and IGFBPL1) showed association with overall survival in different PDAC cohorts. Interestingly, overexpression of FGF14 was found associated with better overall survival (OS) in all three cohorts. Of note, multivariate analysis also revealed FGF14 as an independent prognostic marker for better OS in all three cohorts. Furthermore, FMN2 and PGR were among the top genes that correlated with FGF14 in all 3 cohorts. Of note, overexpression of FMN2 and PGR was found significantly associated with good overall survival in PDAC patients, suggesting FMN2 and PGR can also act as potential markers for the prediction of prognosis in PDAC patients.ConclusionFGF14 may define a distinct subset of PDAC patients with better prognosis. Moreover, FGF14-based sub-classification of PDAC suggests that FMN2 and PGR can be employed as good prognostic markers in PDAC and this classification may lead to new therapeutic approaches.

PALB2 upregulation is associated with a poor prognosis in pancreatic ductal adenocarcinoma.

During DNA repair, BRCA1 and BRCA2 interact with the tumor suppressor partner and localizer of BRCA2 (PALB2). PALB2 mutations are associated with an increased risk of breast and ovarian carcinoma, and upregulated PALB2 expression is associated with poor clinical outcomes. The present study investigated the role and prognostic value of PALB2 in pancreatic ductal adenocarcinoma (PDAC). PALB2 expression was inhibited using a small interfering RNA in PDAC cell lines, and the subsequent effects on cell proliferation and migration were investigated. Tissue microarrays from 157 patients undergoing a pancreaticoduodenectomy for PDAC were analyzed via immunohistochemistry, and PALB2 expression was compared with patient outcomes using Kaplan-Meier curves and the multivariate Cox regression model. PALB2-knockdown in PDAC cells had little effect on cell proliferation, but significantly decreased cell migration. Relatively high PALB2 expression was observed in PDAC tissues compared with in peritumoral tissues. Overall survival (OS) was negatively associated with PALB2 expression. TNM stage and PALB2 expression were identified as independent prognostic factors associated with OS via multivariate analysis. Overall, the present study demonstrated that PDAC cell migration was dependent on PALB2, which was further supported by the finding that elevated PALB2 expression in PDAC tissues was associated with poor survival in patients with PDAC. Therefore, PALB2 may serve as a novel prognostic marker in PDAC, which may aid with the development of therapeutic strategies for the disease.

Shorter Treatment-Naïve Leukocyte Telomere Length is Associated with Poorer Overall Survival of Patients with Pancreatic Ductal Adenocarcinoma.

Critically shortened telomeres contribute to chromosomal instability and neoplastic transformation and are associated with early death of patients with certain cancer types. Shorter leukocyte telomere length (LTL) has been associated with higher risk for pancreatic ductal adenocarcinoma (PDAC) and might be associated also with survival of patients with PDAC. We investigated the association between treatment-naïve LTL and overall survival of patients with incident PDAC. The study included 642 consecutively enrolled PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreas Research. Blood samples were obtained at the time of diagnosis, before the start of cancer treatment, from which LTL was assayed by qRT-PCR. LTL was first modeled as a continuous variable (per-interquartile range decrease in LTL) and then as a categorized variable (short, medium, long). Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated for overall mortality using Cox proportional hazard models. Shorter treatment-naïve LTL was associated with higher mortality among patients with PDAC (HRcontinuous = 1.13, 95% CI: 1.01-1.28, P = 0.03; HRshortest vs. longest LTL = 1.29, 95% CI: 1.05-1.59, P trend = 0.01). There was a difference in the association between LTL and overall mortality by tumor stage at diagnosis; resectable tumors (HRcontinuous = 0.91; 95% CI: 0.73-1.12), locally advanced tumors (HRcontinuous = 1.29; 95% CI: 1.07-1.56), and metastatic tumors (HRcontinuous = 1.17; 95% CI: 0.96-1.42), P interaction = 0.04. Shorter treatment-naïve LTL is associated with poorer overall survival of patients with incident PDAC. Peripheral blood LTL might be a prognostic marker for PDAC.

Association of Neutrophil, Platelet, and Lymphocyte Ratios with the Prognosis in Unresectable and Metastatic Pancreatic Cancer.

We examined the relationship between the daily rate of change of cancer antigen 19-9 (CA19-9) over the first 90 days of treatment (DRC90) and the pretreatment levels of neutrophils, lymphocytes, and platelets with the overall survival (OS) and progression-free survival (PFS) in patients with stage IV pancreatic ductal adenocarcinoma (PDA) who received chemotherapy. We retrospectively evaluated 102 locally advanced and metastatic PDA patients treated at the University of Kansas Cancer Center (KUCC) between January 2011 and September 2019. We compared the ratio of the pretreatment absolute neutrophil count to the pretreatment absolute lymphocyte count (NLR) and the ratio between the pretreatment platelet count to the pretreatment absolute lymphocyte count (PLR) with the OS and PFS. We compared the DRC90 to the OS and PFS. The ratios were analyzed using the log-rank trend test using the mean of the NLR, PLR, and DRC90 as the threshold for two groups within each variable. Patients with ≥mean NLR (4.6 K/µL) had a significantly lower OS (p = 0.0444) and PFS (p = 0.0483) compared with patients below the mean. Patients with PLR ≥ mean (3.9 K/µL) did not have a significantly different OS (p = 0.507) or PFS (p = 0.643) compared with patients below the mean. Patients with DRC90 ≥ mean (−1%) did not have a significantly different OS (p = 0.342) or PFS (p = 0.313) compared with patients below the mean. Patients with NLR ≥ mean (4.6 K/µL) had a significantly lower OS and PFS compared with patients with NLR below the mean. This implies the possibility of NLR as a prognostic marker in PDA that could guide treatment approaches but still requires validation in a larger cohort.

TLE2 is associated with favorable prognosis and regulates cell growth and gemcitabine sensitivity in pancreatic cancer.

BackgroundThe transducin-like enhancer of split (TLE) proteins are a group of transcriptional corepressors. They play a crucial role in cellular homeostasis and are involved in various cancers. Compared with other TLE family members, little is known about the role and the underlying mechanism of TLE2 in human cancers. This study aimed to investigate the role of TLE2 in pancreatic ductal adenocarcinoma (PDAC) using in silico analysis and in vitro experiments.MethodsData were obtained from the Cancer Genome Atlas (TCGA) database to evaluate the prognostic value of TLE2 in PDAC. The MiaPaCa-2 cell line was transfected with siRNA to inhibit endogenous TLE2 expression, and a PANC-1 cell line with stable TLE2 overexpression was constructed using lentiviral transfection, which were confirmed by real-time polymerase chain reaction and western blotting. MTT assay, transwell invasion assays, and flow cytometry were carried out to assess cell viability, invasion, and apoptosis, respectively. TLE2 expression in PDAC cells was altered to evaluate their sensitivity to gemcitabine. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to predict the biological role of TLE2.ResultsHigh expression of TLEs was significantly associated with increased overall survival (OS) and disease-free survival (DFS) in patients with PDAC. Among the PDAC cell lines, TLE2 expression was lowest and highest in PANC-1 cells and MiaPaCa-2 cells, respectively. TLE2 overexpression impaired the proliferation ability of PANC-1 cells and downregulation of TLE2 promoted the proliferation of MiaPaCa-2 cells. Upregulation of TLE2 in PANC-1 cells induced S-phase accumulation and sensitivity to gemcitabine. In contrast, the downregulation of TLE2 in MiaPaCa-2 cells promoted resistance to gemcitabine. Moreover, bioinformatics analysis also revealed the potential tumor suppressor role of TLE2 and uncovered a close relationship between TLE2 expression and cell cycle regulation.ConclusionsOur results suggest that TLE2 expression is correlated with prognosis in patients with PDAC and show that TLE2 plays a central role in the regulation of cell proliferation, the cell cycle, and gemcitabine sensitivity. This study provides new insights and evidence that TLE2 functions as a tumor suppressor gene and prognostic marker in PDAC.

Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.

Association of neutrophil, platelet, and lymphocyte ratios with prognosis in metastatic pancreatic cancer.

767 Background: High mortality associated with pancreatic ductal adenocarcinoma (PDA) warrants research into prognostic factors. We examined the relationship between the daily rate of change of CA19-9 over the first 90 days of treatment (DRC90) and pretreatment levels of neutrophils, lymphocytes, and platelets with overall survival (OS) and progression free survival (PFS) in patients with stage IV PDA that received chemotherapy. Methods: We retrospectively evaluated 102 locally advanced and metastatic PDA patients treated at KU Cancer Center between Jan 2011 and Sep 2019. We compared the ratio of pretreatment absolute neutrophil count to pretreatment absolute lymphocyte count (NLR) and the ratio between pretreatment platelet count to pretreatment absolute lymphocyte count (PLR) with OS and PFS. We also compared DRC90 to OS and PFS. Log-rank trend test using the mean of NLR, PLR, and DRC90 as the threshold for two groups within each variable. Results: Baseline demographics are shown in the table. Pts with ≥ mean NLR (4.6) had significantly lower OS [p = 0.0444] and PFS [p = 0.0483] than Pts below the mean. Pts with PLR ≥ mean (3.9) did not have significantly different OS [p = 0.507] or PFS [p = 0.643] than Pts below the mean. Pts with DRC90 ≥ mean (-1%) did not have significantly different OS [p = 0.342] or PFS [p = 0.313] than Pts below the mean. Conclusions: Pts with NLR ≥ mean (4.6) had significantly lower OS and PFS than Pts with NLR below the mean. This implies the possibility of NLR as a prognostic marker in PDA that could guide treatment approach but needs validation in a larger cohort. [Table: see text]

The GALNT14 Genotype Predicts Postoperative Outcome of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is notorious for its poor prognosis. The current mainstay of treatment for PDA is surgical resection followed by adjuvant chemotherapy. However, it is difficult to predict the post-operative outcome because of the lack of reliable markers. The single-nucleotide polymorphism (SNP) of N-acetylgalactosaminyltransferase14 (GALNT14) has been proven to predict the progression-free survival (PFS), overall survival (OS) and response to chemotherapy in various types of gastrointestinal (GI) cancers. However, its role in PDA has not been studied. This study aims to investigate whether the GALNT14 SNP genotype can be a prognostic marker for PDA. A cohort of one hundred and three PDA patients having received surgical resection were retrospectively enrolled. GALNT14 genotypes and the clinicopathological parameters were correlated with postoperative prognosis. The genotype analysis revealed that 19.4%, 60.2% and 20.4% of patients had the GALNT14 “TT”, “TG” and “GG” genotypes, respectively. The patients with the “GG” genotype had a mean OS time of 37.1 months (95% confidence interval [CI]: 18.2–56.1) and those with the “non-GG” genotype had a mean OS time of 16.1 months (95% CI: 13.1–19.2). Kaplan–Meier analysis showed that the “GG” genotype had a significantly better OS compared to the “non-GG” genotype (p = 0.005). However, there was no significant difference between the “GG” and “non-GG” genotypes in PFS (p = 0.172). The baseline characteristics between patients with the “GG” and “non-GG” genotypes were compared, and no significant difference was found. Univariate followed by multivariate Cox proportional hazard models demonstrated the GALNT14 “GG” genotype, negative resection margin, and locoregional disease as independent predictors for favorable OS (p = 0.003, p = 0.037, p = 0.021, respectively). Sensitivity analysis was performed in each subgroup to examine the relationship of GALNT14 with different clinicopathological variables and no heterogeneity was found. The GALNT14 “GG” genotype is associated with favorable survival outcome, especially OS, in patients with resected PDA and could serve as a prognostic marker.

Prognostic significance of EIF4G1 in patients with pancreatic ductal adenocarcinoma.

BackgroundAdvances in genomics have greatly improved the survival rate in cancer patients. However, due to genetic heterogeneity, pancreatic ductal adenocarcinoma (PDAC) is still difficult to diagnose early, and its survival rate is extremely low. Therefore, we identified biomarkers that predict the prognosis of PDAC patients using independent cohort data.Materials and methodsTo develop a novel prognostic biomarker, we used the gene expression and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Kaplan–Meier survival curve using median values of genes as cutoff showed that EIF4G1 was the only statistically significant gene in the 3 cohorts. We analyzed the prognostic significance of EIF4G1 using the time-dependent area under the curve (AUC) of Uno’s C-index, the AUC value of the receiver operating characteristics (ROC) at 3 years, and multivariate Cox analysis. We also compared EIF4G1 levels between tumors and matched non-tumor tissues.ResultsEIF4G1 is the only prognostic gene in patients with PDAC, which was selected by Kaplan–Meier survival analysis. The survival curve showed that high expression of EIF4G1 was associated with poor prognosis of PDAC with a good discriminative ability in 3 independent cohorts. The risk stratifying ability of EIF4G1 was demonstrated by analyzing C-indices and AUC values. Multivariate Cox regression confirmed its prognostic significance. EIF4G1 expression was significantly higher in PDAC tissues than in the matched normal tissues.ConclusionEIF4G1 could be used as a novel prognostic marker for PDAC and to determine suitable treatment options.

Clinical impact of circulating LAPTM4B-35 in pancreatic ductal adenocarcinoma

LAPTM4B is upregulated in a wide range of cancers associated with poor prognosis. However, the clinical impact of LAPTM4B as diagnostic and prognostic marker in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Thus, the aim of the present study was to investigate the expression of LAPTM4B as circulating marker in PDAC. Expression analysis of LAPTM4B-35 in pancreatic tissue and preoperative blood serum samples of 169 patients with PDAC UICC Stages I-IV (n = 98), chronic pancreatitis (n = 41), and healthy controls (n = 30) by immunohistochemistry, Western blot, and ELISA. Descriptive and explorative statistical analyses of LAPTM4B-35's potential as diagnostic and prognostic marker in PDAC. Expression of LAPTM4B-35 was significantly increased in tumor tissue and corresponding blood serum samples of patients with PDAC (each p < 0.001) and it could well discriminate PDAC from healthy controls and chronic pancreatitis (p < 0.001; p = 0.0037). LAPTM4B-35 in combination with CA.19-9 outperforms the diagnostic accuracy with an AUC of 0.903 (p < 0.001), sensitivity of 82%, and specificity of 92%. Kaplan-Meier survival analysis revealed an improved overall survival in PDAC UICC I-IV with low expression of circulating LAPTM4B-35 (17 versus 10 months, p = 0.039) as well as an improved relapse-free survival in curatively treated PDAC UICC I-III (16 versus 10 months; p = 0.037). Multivariate overall and recurrence-free survival analyses identified LAPTM4B-35 as favorable prognostic factor in PDAC patients (HR 2.73, p = 0.021; HR 3.29, p = 0.003). LAPTM4B-35 is significantly deregulated in PDAC with high diagnostic and prognostic impact as circulating tumor marker.

Cytoplasmic TRAIL-R1 is a positive prognostic marker in PDAC

BackgroundThe death receptors TRAIL-R1 and TRAIL-R2 are frequently overexpressed in cancer and there is an emerging evidence for their important role in malignant progression, also in the case of pancreatic ductal adenocarcinoma (PDAC). In their canonical localization at the plasma membrane, TRAIL-R1/−R2 may induce cell death and/or pro-inflammatory signaling leading to cell migration, invasion and metastasis. Although, they have repeatedly been found intracellular, in the cytoplasm and in the nucleus, their functions in intracellular locations are still not well understood. Likewise, studies dealing with the prognostic relevance of TRAIL-Rs located in particular cellular compartments are very rare. For PDAC, the correlation of nuclear TRAIL-R2 with worse patients’ prognosis has been shown recently. Corresponding data on TRAIL-R1 are not available so far.MethodsIn the present study we analyzed the expression of TRAIL-R1 in 106 PDACs and 28 adjacent, peritumoral non-malignant pancreatic ducts with special emphasis on its cytoplasmic and nuclear localization and correlated the immunohistochemical findings with clinico-pathological patient characteristics.ResultsTRAIL-R1 was found in 93.4% of all PDAC samples. Cytoplasmic staining was present with very similar intensity in tumor and normal tissue. In contrast, nuclear TRAIL-R1 staining was significantly stronger in tumor compared to normal tissue (p = 0.006). Interestingly, we found that the number of cells with cytoplasmic TRAIL-R1 staining negatively correlates with tumor grading (p = 0.043). No such correlation could be detected for nuclear TRAIL-R1. Neither, cytoplasmic nor nuclear TRAIL-R1 staining showed a correlation with other clinico-pathological parameter such as pTNM categories. However, Kaplan-Meier analyses revealed significantly prolonged median survival of patients with positive cytoplasmic TRAIL-R1 expression in more than 80% of tumor cells compared to patients with tumors containing a smaller quantity of cells positively stained for cytoplasmic TRAIL-R1 (20 vs. 8 months; p = 0.004).ConclusionCytoplasmic TRAIL-R1 is a positive prognostic marker for patients with PDAC. Our findings indicate that loss of cytoplasmic TRAIL-R1 results in recurrent disease with more malignant phenotype thus suggesting anti-tumor activities of cytoplasmic TRAIL-R1 in PDAC.