Expression data from human lung FFPE samples
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE211528 | GEO | 2023/05/26
REPOSITORIES: GEO
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Project description:Nasopharyngeal carcinoma (NPC) is a challenging cancer that is rare in the United States but shows exceptionally high incidence in Southern China, Indonesia, and Malaysia. While the hallmark of NPC is striking geographic variation, early detection and clinical management are also critical characteristics of this cancer. The etiology of NPC is complex, involving the interplay of multiple factors, including Epstein Barr Virus (EBV), which appears to play an oncogenic role. While multimodality therapy is the mainstay of treatment for NPC, the impact of this treatment is greatly influenced by the presenting tumor stage, tumor size, nodal involvement, and the histologic subtype classification. Up to 40% percent of NPC cases present at an advanced stage, likely due to its deep location in the lymphatic-rich nasopharynx and its propensity for early lymphatic spread. Recent modifications in the TNM staging schema have attempted to improve prognostic accuracy, but variations in clinical outcome are still reported in patients with the same stage and similar treatment regimens. The various molecular markers developed to monitor disease progression have also proven unreliable. Hence, there is a significant need for a new kind of prognostic biomarker for NPC. Herein different approaches were applied to a set of samples to detect NPC-related miRNAs, potential circulating biomarkers. We have optimized the extraction of total RNA from NPC Formalin-fixed, paraffin-embedded (FFPE) samples and sera from four patients and matched controls and analyzed the miRNA expression profile by microarray, qPCR and RNAseq. The microarray analysis showed that 46 miRNAs were found to be differentially and significantly expressed in carcinogenic tissue compared to healthy tissue. Twenty-three (23) microRNAs were significantly upregulated (21 human microRNAs and 2 EBV miRNAs), whereas 13 were down-regulated.
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Project description:Purpose: Gene expression signatures developed to measure the activity of oncogenic signaling pathways have been used to dissect the heterogeneity of tumor samples and to predict sensitivity to various cancer drugs that target components of the relevant pathways, thus potentially identifying therapeutic options for subgroups of patients. To facilitate broad use, including in a clinical setting, the ability to generate data from formalin-fixed, paraffin-embedded (FFPE) tissues is essential. Experimental Design: Patterns of pathway activity in matched fresh-frozen and FFPE xenograft tumor samples were generated using the MessageAmp Premier methodology in combination with assays using Affymetrix arrays. Results generated were compared with those obtained from fresh-frozen samples using a standard Affymetrix assay. In addition, gene expression data from patient matched fresh-frozen and FFPE melanomas were also utilized to evaluate the consistency of predictions of oncogenic signaling pathway status. Results: Significant correlation of pathway activity predictions was observed between paired fresh-frozen and FFPE xenograft tumor samples. In addition, significant concordance of pathway activity predictions was also observed between patient matched fresh-frozen and FFPE melanomas. Conclusion: Reliable and consistent predictions of oncogenic pathway activities can be obtained from FFPE tumor tissue samples. The ability to reliably utilize FFPE patient tumor tissue samples for genomic analyses will lead to a better understanding of the biology of disease progression and, in the clinical setting, will provide tools to guide the choice of therapeutics to those most likely to be effective in treating a patient’s disease.
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Project description:Chemoradiation prior to surgery in locally advanced rectal cancer is the current standard therapy. Unfortunately, this is not effective in all rectal cancer patients and associated with severe side effects, thus, prognostic marker molecules predicting the effectiveness of radiation would be of great interest. Aim of this study was to investigate pathophysiological mechanisms underlying radioresistance. Therefore, FFPE rectal tumor (n=50) and control tissue (n=39) of non-responders and responders to chemoradiation were analyzed using LC-MS-based proteomics. As a result, 1683 proteins were robustly identified. Comparing tumor with corresponding control samples revealed 199 significantly regulated proteins with FTL, PCOLCE and RCN3 being most striking in tumor tissue. While CAECAM 1, 5 and 6 as well as MCM protein complex components were significantly up-regulated in tumor tissue of non-responders compared to all types of responders, ER-stress and autophagic activity-related proteins, namely HYOU1, PDIA4 and RAB1B were only found significantly regulated when compared to complete responders, suggesting their importance in radioresistance mechanisms. Analyzing not only tumor but also surrounding control tissue allowed us to highlight the contribution of stroma to radioresistance. This study demonstrates the suitability of FFPE samples for proteomic analysis and presents potential molecular mechanisms mediating resistance to chemoradiation in rectal cancer.
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2019-05-20 | PXD012694 | Pride
Project description:Recently it was shown that gene expression signatures generated from DNA microarray analyses have promise as biomarkers of clinical outcome and that the molecular characteristics of tumors could be elucidated. Through this study, we have determined a high-risk signature for recurrence as a prognostic biomarker using formalin-fixed HNSCC tumors and tested the results to an independent data set obtained from fresh frozen tumors as a comparison. Also, we have shown the genes that are involved in epithelial to mesenchymal transition and nuclear factor-ĸB signaling deregulation are the most prominent molecular characteristics of the high-risk tumors. Forty samples including 34 formalin-fixed tissues and 6 matched frozen tissues from 29 HNSCC patients were analyzed for gene expression. The formalin-fixed tumors were classified based on their gene expression by intrinsic analysis and the intrinsic gene list was tested on the classification of previously published 60 frozen HNSCC tumors which highly correlated. Based on the molecular classification, a 75-gene list that is predictive of high-risk for recurrence was determined by training on the formalin-fixed tumor set and tested on the independent frozen tumor set. The difference in recurrence-free survival (RFS) between the high-risk vs. low-risk groups in the training and test sets were statistically significant (Log-rank test, p=0.002 and p=0.03, respectively). Also, the gene expression data was interrogated using Gene Set Enrichment Analysis to determine functional significance. The most significant sets of genes that are enriched in the high-risk tumors were genes involving epithelial to mesenchymal transition (EMT), NF-ĸB activation and cell adhesion. In conclusion, global gene expression analysis is feasible using formalin-fixed tissue, and the data from different sample preparations and array platforms can be reliably combined for analyses. The 75-gene list can be utilized as a prognostic biomarker of recurrence and the molecular characteristics of EMT and NF-ĸB activation can be targeted as the novel therapy in the identified high-risk patients. Keywords: FFPE, survival analysis
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Project description:Background: The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n=302), we now functionally assess the mechanistic role of a novel driver, PARP4. Methods: In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4’s interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. Results: PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4’s tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. Conclusions: PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex – unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.
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