Expression profiles for 14-3-3 zeta and CCL20 in pancreatic cancer and chronic pancreatitis

Background: Pancreatic cancer (PCA) has a dismal prognosis because it is often diagnosed at an advanced stage. The overall survival rate is < 5% after five years. Chronic pancreatitis (CP) is one of the most important risk factors for PCA. A major difficulty is to distinguish between CF and PCA at both clinical and morphologic level. The aim of this study was to assess the impact of the expression profiles for 14-3-3 zeta and CCL20 to histologically discriminate between PCA and CP. Methods: In PCA (n = 138) and CF (n = 36) tissue samples, the expression of 14-3-3 zeta and CCL20 was examined by immunohistochemistry. Associations between expression profiles of 14-3-3 zeta and CCL20 expression in PCA, CP as well as MANT (matched adjacent normal tissue) (n = 138) and clinicopathologic variables were analyzed. Results: The expression of CCL20 and 14-3-3 zeta was significantly higher in PCA than in CP and MANT. For CF compared to MANT, no significant differences were observed for expression profiles of both 14-3-3 zeta and CCL20. Conclusion: CCL20 and 14-3-3 zeta are molecules that play a putative role during tumorgenesis in pancreas, and may therefore be new parameters for histological diagnosis and discrimination between PCA and CP. (C) 2014 Elsevier GmbH. All rights reserved

Alterations of Global Histone H3K9 and H3K27 Methylation Levels in Bladder Cancer

Background: Epigenetic alterations, including histone modifications, play an important role during carcinogenesis. This study was designed to systematically investigate histone H3K9 and H3K27 methylation levels in bladder cancer (BCa) tissue. Methods:A tissue microarray with urothelial BCa (150 non-muscle-invasive BCa, NMIBC; 121 muscle-invasive BCa, MIBC; 31 metastatic BCa, MET) and normal urothelium (29, CTRL) specimen was used to determine the global levels of H3K9 and H3K27 mono-, di- and tri-methylation. Results: Global levels of H3K9 and H3K27 methylation were significantly higher in CTRL than in BCa, and levels in NMIBC were higher compared to MIBC. Histone nnethylation levels of MET resembled MIBC. We observed furthermore a correlation of histone nnethylation levels with pT stage (H3K9me1, H3K9me2, H3K9me3, H3K27me1, H3K27me3) and grade (H3K9nne2, H3K9me3, H3K27nne1) in NMIBC. H3K9me1, H3K9me3, H3K27me1 and H3K27me3 levels were also correlated with pT stage in MIBC. Histone modifications were not associated with recurrence-free or cancer-specific survival. Conclusions: Global histone H3K9 and H3K27 nnethylation levels are altered in BCa. (C) 2014 S. Karger AG, Base

Fibroblast growth factor receptor-1 as a potential therapeutic target in sinonasal cancer

Background. Despite multimodal treatment, sinonasal malignancies have an unfavorable prognosis. The purpose of this study was to elucidate if these tumors harbor amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, which has recently been identified as a potential therapeutic target in squamous cell lung cancer. Methods. One hundred twelve primary tumors (including squamous cell carcinoma [SCC], carcinoma associated with an inverted papilloma, sinonasal undifferentiated carcinoma [SNUC], adenocarcinoma, adenoid cystic carcinoma [ACC], esthesioneuroblastoma, and 9 corresponding lymph node metastases) were assessed by fluorescence in situ hybridization (FISH) for FGFR1 copy number status. Human papillomavirus (HPV) status was assessed by p16 immunohistochemical as a surrogate marker. Results. FGFR1 amplification was found in subsets of sinonasal SCCs (20%), carcinomas associated with an inverted papilloma (33%), and SNUCs (5%). In all cases, metastatic tumor samples shared the same FGFR1 amplification status as the corresponding primary tumor tissue. None of the FGFR1-amplified tumors expressed p16. Conclusion. FGFR1 amplification represents a potential molecular target in a subset of patients with sinonasal cancer. (C) 2014 Wiley Periodicals, Inc

Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer

We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio >= 2.0, or average number of FGFR1 signals per tumor cell nucleus >= 6, or the percentage of tumor cells containing >= 15 FGFR1 signals or large clusters >= 10%) was detected at a frequency of 16% and low-level amplification (as defined by >= 5 FGFR1 signals in >= 50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials. Modern Pathology (2012) 25, 1473-1480; doi: 10.1038/modpathol.2012.102; published online 8 June 201