Project description:Abstract Background The aim of this study was to identify prognostic molecular biomarkers to neoadjuvant chemoradiotherapy (nCRT) in locally advanced oral cavity cancer (LA-OCC) on a transcriptome level. Materials and methods The global transcriptome of therapy-naïve LA-OCC treated within the prospective INVERT trial by nCRT were used as a discovery cohort for massive analysis of cDNA Ends (MACE) from archived biopsy specimen (n = 17; patients received nCRT consisting of 60 Gy with concomitant platinum based chemotherapy six to eight weeks preoperatively [3]) was investigated. Potential predictive biomarkers (EpCAM and Sox2) were further verified on an independent retrospective explorative tissue microarray (TMA) cohort of tumor and matched non-tumor specimen of primarily surgically resected HNSCC patients (n = 240). The biomarker expression was associated with clinicopathological features and outcome of the patients in our explorative tumor cohort. Results Deregulated transcripts between tumor tissue of patients with complete or incomplete response to the INVERT therapy regimen in our discovery cohort were shown regarding cell cycle G1/S transition, Wnt signaling, and epithelial adhesion and differentiation. Confirmation of altered expression of EpCAM on a protein level with high EpCAM expression was associated with impaired overall survival. The prognostic relevance of elevated EpCAM expression was also confirmed using the independent explorative cohort (p = 0.044). Additional Sox2 staining correlated significantly with EpCAM expression (p < 0.001) and EpCAM might serve as a risk factor for worse overall survival in our explorative cohort (p = 0.049). However, EpCAM did not serve as an independent risk factor in this cohort. Conclusion Transcriptomic profiling of therapy-naïve LA-OCC revealed biological processes and pathways that could be associated with therapy response and impaired overall survival. By translating results into readily available daily routine biomarkers, histopathological-based EpCAM and Sox2 assessment could support prognostication of patient overall survival. Prospective trials are necessary to validate this result using tissue and liquid biopsy-based approaches.

Project description:Rationale: Steroids are the mainstay of asthma therapy. However, it is unclear whether the benefits of steroids in asthma are merely based on anti-inflammatory properties. Steroids may also alter gene expression of airway smooth muscle (ASM). Hypothesis and Aims: We hypothesized that the transcriptomic profile of the ASM layer in endobronchial biopsies of atopic asthma patients changes by oral steroid therapy. First, we examined the change in ASM transcriptomic profile in endobronchial biopsies after 14 days of oral steroid therapy. Second, we investigated the association between changes in ASM transcriptomic profile and airway function. Methods: 12 atopic steroid-free asthma patients were included in this double-blind intervention study. Endobronchial biopsies were taken before and after 14 days of oral prednisolon (n=6) or placebo (n=6). RNA of laser-dissected ASM was sequenced (RNA-Seq) using the GS FLX+ System (454/Roche). Gene networks were identified using Ingenuity Pathway Analysis. RNA-Seq reads were assumed to follow a negative binomial distribution. At the current sample size the estimated false discovery rate was approximately 3%. Results: 15 genes were significantly changed by 14 days of oral prednisolon. 2 of these genes (FAM129A, SYNPO2) were associated with the methacholine PC20 (r=0.637, p=0.035; r=0.662, p=0.027). Pathway analysis revealed 3 gene networks that were associated with cellular functions including cellular growth, proliferation, and development. Conclusion: Oral prednisolon changes the gene expression profile of the ASM layer in asthma. This indicates that steroids also exert effects on the transcriptomic level of ASM in addition to their anti-inflammatory properties, which can promote improved airway function. The current randomized, double-blind, parallel, placebo-controlled intervention study comprised 4 visits. At visit 1, asthma patients were screened according to the in- and exclusion criteria prior to enrollment. Additionally, spirometry and methacholine bronchoprovocation test were performed. At visit 2, FEV1 reversibility was measured and endobronchial biopsies were collected during a bronchoscopy. Asthma patients were then prescribed oral prednisolon at a dose of 0.5 mg/kg per day or placebo for 14 consecutive days. The dosage and dosing scheme was based on international recommendations for the treatment of acute exacerbations [1]. On the 11th day after visit 2, the patients visited the lung function laboratory for spirometry and methacholine bronchoprovocation test. Finally, at visit 4 (15th day after visit 2) FEV1 reversibility was measured and endobronchial biopsies were collected by bronchoscopy. Airway smooth muscle was collected from the biopsies by laser capture microdissection and total RNA isolated. cDNA was prepared using the Ovation RNA-Seq System (NuGEN). RNA-Seq was performed using the GS FLX+ instrument (454/Roche). Sequence reads were mapped against the human genome (hg19; UCSC). Comparison of the numbers of reads per gene between the prednisolon and placebo study group was carried out with the R package DESeq.

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