Overall Survival Of Pancreatic Cancer Patients Research Articles

FoxQ1 is a Novel Molecular Target for Pancreatic Cancer and is Associated with Poor Prognosis.

FOXQ1 is an oncogene for a variety of tumors and encodes the forkhead boxrelated transcription factor FoxQ1. However, little is known about the role of FoxQ1 in pancreatic cancer (PC). In this study, we examined FoxQ1 expression in PC cell lines and human PC tissues by quantitative PCR and tissue microarray based immunohistochemical staining (IHC), and investigated the clinical correlation between FoxQ1 tissue levels and the clinicopathological characteristics of PC patients. We found that FoxQ1 mRNA expression was up-regulated both in PC cell lines and tumor tissues. IHC results revealed that FoxQ1 was mainly expressed in the cytoplasm, and to a lesser extent in the nucleus of PC cells. FoxQ1 protein levels were significantly higher in PC tissues when compared with matched non-cancerous tissues, and associated positively with the degree of tumor differentiation. Univariate and multivariate survival analysis revealed that patients with high FoxQ1 expression and advanced TNM stage had poor prognosis (HR=1.856, 95%CI 1.065- 3.234, P=0.029; HR=2.091, 95%CI 1.181-3.705, P=0.01). These data indicate that FoxQ1 expression is negatively associated with the overall survival of PC patients, and that this protein may therefore represent a novel molecular target and new prognostic biomarker for PC.

Circulating nucleosomes and immunogenic cell death markers HMGB1, sRAGE and DNAse in patients with advanced pancreatic cancer undergoing chemotherapy

Serum biomarkers are urgently needed for patient stratification and efficient treatment monitoring in pancreatic cancer (PC). Within a prospective diagnostic observation study, blood samples were obtained from 78 patients with advanced PC before and weekly during the course of palliative chemotherapy. Circulating nucleosomes and immunogenic cell death markers, high-mobility group box 1 (HMGB1), soluble receptors of advanced glycation end products (sRAGE) and DNAse activity, were measured by enzyme-linked immunosorbent assay and correlated with results of radiological staging after 2 months of treatment, with time to progression (TTP) and overall survival (OS). Median TTP and OS of PC patients were 3.9 and 7.7 months, respectively. Pretherapeutic baseline biomarker levels did not correlate with objective response; however, nucleosome levels on day (d) 28 were higher (p = 0.048) and sRAGE levels at time of staging (d56) were lower in progressive patients (p = 0.046). Concerning estimation of prognosis, high nucleosome levels (d7, d14, d21 and d56), low sRAGE levels (d56) and DNAse activity courses (d0-d7) correlated with TTP, whereas high nucleosomes (d7, d14 and d56), high HMGB1 (d21 and d56) and DNAse (d0-d7) were associated with OS. After adjustment to Karnofsky performance score, nucleosomes and HMGB1 (both d56) and DNAse (d0-d7) remained independent prognostic factors. Thus, courses of circulating nucleosomes and immunogenic cell death markers HMGB1 and sRAGE show prognostic relevance in PC patients undergoing chemotherapy.

Array-based comparative genomic hybridization analysis to identify prognostic markers for resected pancreatic cancer.

4097 Background: The clinical relevance of genomic imbalances in pancreatic cancer is uncertain. The aim of this study was to evaluate whether alterations in specific genes influenced clinical outcome in resected pancreatic cancer patients. Methods: Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens from a Korean cohort, including 24 patients who received adjuvant chemotherapy regimens with gemcitabine or 5-fluorouracil. Statistical analysis enabled us to assess the interaction of copy number alterations with clinicopathological variables and overall survival (OS). Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent Italian cohort of 61 resected pT3N1Mx stage pancreatic cancers treated with gemcitabine adjuvant therapy. Results: Recurrent copy number gains were observed in chromosome 1q, 11q, 18q11.1-11.2, and 20q13.13; and losses in chromosome 2p, 9p, 10q, 14q, 15q, 18q12.2-23, 19q, 20q11.1, 21p, and 22q. Loss of cytoband 18q22.3 (in 8 patients) was significantly more frequent in patients surviving shorter than the median OS (p=0.021, Fisher-Exact test). This cytoband encodes 5 genes, including CNDP2, whose copy number was associated with OS (p=0.019, log-rank test). The copy number of this gene was subsequently assessed in the Italian cohort, where patients with deletion (N=41) had shorter OS (p=0.003, log-rank test). Multivariate analysis of the two cohorts showed that loss/deletion of 18q22.3/CNDP2 was an independent poor prognostic factor for OS (hazard ratio 2.72, p=0.0007) after adjusting for other factors influencing clinical outcome. Conclusions: Through aCGH analysis, we identified loss/deletion of 18q22.3/CNDP2 as a potentialindependent poor prognostic factor in resected pancreatic cancer. Given the heterogeneity of the two cohorts, further confirmation on a large number of patients is warranted. However, the combined Cox model suggests that this genetic alteration may have a meaningful impact on OS of pancreatic cancer patients, and its biological implications are being investigated.

DNA Mismatch Repair Gene Polymorphisms Affect Survival in Pancreatic Cancer

DNA mismatch repair (MMR) maintains genomic stability and mediates cellular response to DNA damage. We aim to demonstrate whether MMR genetic variants affect overall survival (OS) in pancreatic cancer. Using the Sequenom method in genomic DNA, we retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 MMR genes from 706 patients with pancreatic adenocarcinoma seen at The University of Texas MD Anderson Cancer Center. Association between genotype and OS was evaluated using multivariable Cox proportional hazard regression models. At a false discovery rate of 1% (p ≤ .0015), 15 SNPs of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, TP73, and TREX1 in patients with localized disease (n = 333) and 6 SNPs of MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease (n = 373) were significantly associated with OS. In multivariable Cox proportional hazard regression models, SNPs of EXO1, MSH2, MSH3, PMS2L3, and TP73 in patients with localized disease, MSH2, MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease, and EXO1, MGMT, MSH2, MSH3, MSH6, PMS2L3, and TP73 in all patients remained significant predictors for OS (p ≤ .0015) after adjusting for all clinical predictors and all SNPs with p ≤ .0015 in single-locus analysis. Sixteen haplotypes of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, RECQL, TP73, and TREX1 significantly correlated with OS in all patients (p ≤ .001). MMR gene variants may have potential value as prognostic markers for OS in pancreatic cancer patients.