Molecular markers associated with outcome and metastasis in human pancreatic cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42952 | GEO | 2013/01/09
SECONDARY ACCESSION(S): PRJNA183966
REPOSITORIES: GEO
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer in which differences in survival rates might be related to a variety in gene expression profiles. Although the molecular biology of PDAC begins to be revealed, genes or pathways that specifically drive tumour progression or metastasis are not well understood. Therefore, we performed microarray analyses on whole-tumour samples of 2 human PDAC subpopulations with similar clinicopathological features, but extremely distinct survival rates after potentially curative surgery, i.e., good outcome (OS and DFSM-bM-^@M-^I>M-bM-^@M-^I50M-bM-^@M-^Imonths) versus bad outcome (OSM-bM-^@M-^I<M-bM-^@M-^I19M-bM-^@M-^Imonths and DFSM-bM-^@M-^I<M-bM-^@M-^I7M-bM-^@M-^Imonths). Additionally, liver- and peritoneal metastases were analysed and compared to primary cancer tissue. The integrin and ephrin receptor families were upregulated in all PDAC samples, irrespective of outcome, supporting an important role of the interaction between pancreatic cancer cells and the surrounding desmoplastic reaction in tumorigenesis and cancer progression. Moreover, some components, such as ITGB1 and EPHA2, were upregulated in PDAC samples with a poor outcome, Additionally, overexpression of the non-canonical Wnt/M-NM-2-catenin pathway and EMT genes in PDAC samples with bad versus good outcome suggests their contribution to the invasiveness of pancreatic cancer, with M-NM-2-catenin being also highly upregulated in metastatic tissue. Thus, we conclude that components of the integrin and ephrin pathways and EMT-related genes might serve as molecular markers in pancreatic cancer as their expression seems to be related with prognosis. Microarray analysis was performed on 'Good' and 'Bad' patient samples (samples with similar pathological characteristics were chosen based on the definition of the 2 diverse survival outcome groups and the required RIN values above 7.1), on surrounding non-tumoural pancreatic control samples, liver metastasis (LM) and peritoneal metastasis (PM). Comparisons between good vs. control, bad vs. control, good vs. bad, and primary pancreatic cancer versus metastasis were performed.
2013-01-09 | E-GEOD-42952 | biostudies-arrayexpress
Project description:Most cancer deaths are caused by metastases, which are the end-results of circulating tumor cells (CTC) that detach from the cancer primary and succeed to survive in distant organs. The aim of the present study was to develop a gene signature of CTC and to assess its prognostic relevance after surgery for pancreatic ductaladenocarcinoma (PDAC). A negative depletion fluorescence activated cell sorting (FACS) procedure was developed and validated with spiking experiments using cancer cell lines in whole human blood samples. This FACS-based method was used to enrich for CTC from the blood of 10 patients who underwent surgery for PDAC. Total RNA was isolated from 4 subgroup samples, i.e. CTC, haematological cells (G), original tumor (T), and non-tumoral pancreatic control tissue (P). After RNA quality control, samples of 6 patients were eligible for further analysis. Whole genome microarray analysis was performed after double linear amplification of RNA. The ‘Ingenuity Pathway Analysis’ software and AmiGO were used for functional data analyses. A CTC gene signature was developed and validated with the nCounter system on expression data of 78 primary PDAC using Cox regression analysis for disease-free (DFS) and overall survival (OS). Using stringent statistical analysis, we finally retained 8,152 genes to compare expression profiles of CTC vs. other subgroups, and found 1,059 genes to be differentially expressed. The pathway with the highest expression ratio in CTC was p38 mitogen-activated protein kinase (p38 MAPK) signaling, known to be involved in cancer cell migration. In the p38 MAPK pathway TGF-β1, cPLA2, and MAX were significantly upregulated. In addition, 9 other genes associated with both p38 MAPK signaling and cell motility were over-expressed in CTC. High co-expression of TGF-1 and our cell motility panel (≥ 4 out of 9 genes for DFS and ≥ 4 out of 9 genes for OS) in primary PDAC was identified as an independent predictor of DFS (p=0.041, HR (95% CI) = 1.885 (1.025 – 3.559)) and OS (p=0.047, HR (95% CI) = 1.366 (1.004 – 1.861)). Pancreatic CTC isolated from blood samples using a FACS-based negative depletion method,express a cell motility gene signature. The expression of this newly defined cell motility gene signature in the primary tumor is able to predict survival of patients who undergo surgical resection for pancreatic cancer. Total RNA was isolated from circulation tumor samples (CTC), haematological cells (G), original tumor (T), and non-tumor pancreatic control tissue (P) of patients with pancreatic ductal adenocarcinoma (PDAC). Gene expression profiles of CTC were compared to G, T, and P. The aim of the current study was to develop a ‘negative depletion strategy’ to isolate CTC without the exclusion of any particular subset of CTC, and to study their gene-expression profiles in order to find novel therapeutic targets and prognostic markers in patients with pancreatic cancer.
2012-12-18 | E-GEOD-18670 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with very frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged disease-free survival (DFS). To date, few studies have determined protein profiles that are associated with responsiveness to adjuvant chemoradiation. Here, we analyzed the proteomes of primary, surgically resected PDAC tumors subjected to adjuvant chemoradiation and achieving short DFS (median DFS of 6 months, n = 6) or a prolonged DFS (median DFS of 28 months, n = 6) using liquid chromatography tandem mass spectrometry.
2018-09-11 | PXD009254 | Pride
Project description:Most cancer deaths are caused by metastases, which are the end-results of circulating tumor cells (CTC) that detach from the cancer primary and succeed to survive in distant organs. The aim of the present study was to develop a gene signature of CTC and to assess its prognostic relevance after surgery for pancreatic ductaladenocarcinoma (PDAC). A negative depletion fluorescence activated cell sorting (FACS) procedure was developed and validated with spiking experiments using cancer cell lines in whole human blood samples. This FACS-based method was used to enrich for CTC from the blood of 10 patients who underwent surgery for PDAC. Total RNA was isolated from 4 subgroup samples, i.e. CTC, haematological cells (G), original tumor (T), and non-tumoral pancreatic control tissue (P). After RNA quality control, samples of 6 patients were eligible for further analysis. Whole genome microarray analysis was performed after double linear amplification of RNA. The ‘Ingenuity Pathway Analysis’ software and AmiGO were used for functional data analyses. A CTC gene signature was developed and validated with the nCounter system on expression data of 78 primary PDAC using Cox regression analysis for disease-free (DFS) and overall survival (OS). Using stringent statistical analysis, we finally retained 8,152 genes to compare expression profiles of CTC vs. other subgroups, and found 1,059 genes to be differentially expressed. The pathway with the highest expression ratio in CTC was p38 mitogen-activated protein kinase (p38 MAPK) signaling, known to be involved in cancer cell migration. In the p38 MAPK pathway TGF-β1, cPLA2, and MAX were significantly upregulated. In addition, 9 other genes associated with both p38 MAPK signaling and cell motility were over-expressed in CTC. High co-expression of TGF-1 and our cell motility panel (≥ 4 out of 9 genes for DFS and ≥ 4 out of 9 genes for OS) in primary PDAC was identified as an independent predictor of DFS (p=0.041, HR (95% CI) = 1.885 (1.025 – 3.559)) and OS (p=0.047, HR (95% CI) = 1.366 (1.004 – 1.861)). Pancreatic CTC isolated from blood samples using a FACS-based negative depletion method,express a cell motility gene signature. The expression of this newly defined cell motility gene signature in the primary tumor is able to predict survival of patients who undergo surgical resection for pancreatic cancer.
2012-12-18 | GSE18670 | GEO
Project description:Background: Only a subset of radically-resected pancreatic ductal adenocarcinoma (PDAC) patients benefit from chemotherapy, and identification of novel prognostic factors is warranted. Recently miRNAs emerged as diagnostic biomarkers and innovative therapeutic targets, while high-throughput arrays are opening new opportunities to evaluate whether they can also predict clinical outcome. The present study evaluated whether comprehensive miRNA expression profiling correlated with overall survival (OS) in resected PDAC patients. Methodology/Principal Findings: High-resolution miRNA profiles were obtained with the Toray’s 3D-GeneTM miRNA chip, detecting more than 1200 types of human miRNA. RNA was isolated from paraffin-embedded primary tumors of 26 radically resected stage-pT3N1 homogeneously treated patients (adjuvant gemcitabine 1000mg/m2/day, days-1/8/15, every 28days), carefully selected according to their outcome (OS<12 vs. OS>30 months, i.e. short/long-OS). Highly stringent statistics included t-test, distance matrix with Spearman-ranked correlation, and iterative approaches. Unsupervised hierarchical analysis revealed that PDAC specimens clustered according to their short/long-OS classification, while the feature selection algorithm RELIEF identified the top-4 discriminating miRNAs between the two groups. These miRNAs target more than 1500 transcripts, including 169 targeted by two or more of these miRNAs. MiR-211 emerged as the best discriminating miRNA, with significantly higher expression in long- vs. short-OS patients. The expression of this miRNA was subsequently assessed by quantitative-PCR in an independent cohort of laser microdissected tumors from 60 resected stage-pT3N1 PDAC patients treated with the same gemcitabine regimen. Patients with low miR-211 expression according to median value had a significantly shorter median OS (14.8, 95%CI=13.1-16.5, vs. 25.7 months, 95%CI=16.2-35.1, log-rank P=0.004). Multivariate analysis demonstrated that low miR-211 expression was an independent factor of poor prognosis (hazard ratio 2.3, P=0.03) after adjusting for all the factors influencing outcome. 19 samples, duplicated gene spots
2012-11-22 | E-GEOD-38781 | biostudies-arrayexpress
Project description:Background: Only a subset of radically-resected pancreatic ductal adenocarcinoma (PDAC) patients benefit from chemotherapy, and identification of novel prognostic factors is warranted. Recently miRNAs emerged as diagnostic biomarkers and innovative therapeutic targets, while high-throughput arrays are opening new opportunities to evaluate whether they can also predict clinical outcome. The present study evaluated whether comprehensive miRNA expression profiling correlated with overall survival (OS) in resected PDAC patients. Methodology/Principal Findings: High-resolution miRNA profiles were obtained with the Toray’s 3D-GeneTM miRNA chip, detecting more than 1200 types of human miRNA. RNA was isolated from paraffin-embedded primary tumors of 26 radically resected stage-pT3N1 homogeneously treated patients (adjuvant gemcitabine 1000mg/m2/day, days-1/8/15, every 28days), carefully selected according to their outcome (OS<12 vs. OS>30 months, i.e. short/long-OS). Highly stringent statistics included t-test, distance matrix with Spearman-ranked correlation, and iterative approaches. Unsupervised hierarchical analysis revealed that PDAC specimens clustered according to their short/long-OS classification, while the feature selection algorithm RELIEF identified the top-4 discriminating miRNAs between the two groups. These miRNAs target more than 1500 transcripts, including 169 targeted by two or more of these miRNAs. MiR-211 emerged as the best discriminating miRNA, with significantly higher expression in long- vs. short-OS patients. The expression of this miRNA was subsequently assessed by quantitative-PCR in an independent cohort of laser microdissected tumors from 60 resected stage-pT3N1 PDAC patients treated with the same gemcitabine regimen. Patients with low miR-211 expression according to median value had a significantly shorter median OS (14.8, 95%CI=13.1-16.5, vs. 25.7 months, 95%CI=16.2-35.1, log-rank P=0.004). Multivariate analysis demonstrated that low miR-211 expression was an independent factor of poor prognosis (hazard ratio 2.3, P=0.03) after adjusting for all the factors influencing outcome.
2012-11-22 | GSE38781 | GEO
Project description:In this study, we performed laser capture microdissection (LCM) of PDAC samples to define their cancer- and stroma-specific molecular subtypes and identify a prognostic gene expression signature for short-term and long-term survival. LCM and RNA-seq analysis of cancer and adjacent stroma of 19 treatment-naïve PDAC tumors were performed. Gene expression signatures were tested for their robustness in a large independent validation set. An RNA in situ hybridization (RNA-ISH) assay with pooled probes for genes associated with disease-free survival (DFS) was developed to probe 111 PDAC tumor samples. Gene expression profiling identified four subtypes of cancer cells (C1-C4) and three subtypes of cancer-adjacent stroma (S1-S3). These stroma-specific subtypes were associated with DFS (p=5.55E-07), with S1 associated with better prognoses when paired with C1 and C2. Thirteen genes were found to be predominantly expressed in cancer cells and corresponded with DFS in a validation using existing RNA-seq datasets. A second validation on an independent cohort of patients using RNA-ISH probes to six of these prognostic genes demonstrated significant association with overall survival (median 17 versus 25 months; p<0.02). Our results identified specific signatures from the epithelial and the stroma components of PDAC, which add clarity to the nature of PDAC molecular subtypes and may help predict survival.
2021-06-30 | GSE164665 | GEO
Project description:Germline BRCA-associated pancreatic ductal adenocarcinoma(glBRCA-PDAC) tumors aresusceptible to platinum/PARP-inhibition. The clinical outcomesof 125 glBRCA-PDAC patients was stratified based on the spectrum of response to platinum/PARP-inhibition: i)Refractory(OS<6 months) ii)Durable response followed by acquired-resistance(OS<36 months); iii)Long-term responders(OS>36 months). Patient-derived-xenografts(PDX) were generated from 25 glBRCA-PDAC patients at different clinical time-points. Response to platinum/PARP-inhibition in-vivo and ex-vivo culture(EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA-PDAC and identified homologous recombination(HR)-proficiency and secondary-mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient(HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor-mutational-burden(TMB) was high in HRD-PDAC and significantly higher in tumors with secondary mutations. Anti-PD1 attenuated tumor growth in a novel humanized glBRCA-PDAC PDX-model. This work demonstrates the utility ofpreclinicalmodels, including EVOC, to predict response of glBRCA-PDAC to treatment, whichhas potential to inform time-sensitive medical decisions.
2023-07-13 | GSE235843 | GEO
Project description:About 50% of resected pancreatic ductal adenocarcinoma (PDAC) recur within just one year following surgery. Prognostic molecular markers predicting rapid recurrence are currently unavailable. We hypothesized that epigenetic differences at the level of chromatin accessibility, potentially linked to distinct differentiation states, might distinguish rapidly recurrent from non-recurrent tumors. Therefore, we interrogated genome-wide chromatin accessibility using Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) on EpCAM+ PDAC malignant cells sorted from a cohort of 54 treatment-naïve resected tumors, in hopes of defining a tumor-intrinsic chromatin signature associated with recurrence. We discovered a signature of ~1000 loci that were differentially accessible between recurrent (disease free survival (DFS) < 1 year) and non-recurrent patients (DFS > 1 year). Through transcription factor (TF) binding motif analysis using supervised learning, we identified candidate TFs whose accessible motifs were differentially associated with recurrence. Nuclear localization of two such TFs as selected by top hits, ZKSCAN1 and HNF1b, were assessed by both immunohistochemistry and immunofluorescence on the tissue microarrays (TMA) of 40 out of 54 patients. Nuclear staining of HNF1b was strong in the non-recurrent and weak or absent in the recurrent patients but ZKSCAN1 was not significantly associated with recurrence. In an independent TMA of PDAC cohort (n=97) preselected for 52 long (OS 6 years)- and 45 short (OS 6 months)- term survivors, the number of nuclear positive cells for HNF1b was 52-fold higher in the long-term compared to the short-term survivors and that for ZKSCAN1 was 5.3-fold higher in the short-term compared to the long-term survivors. Altogether, these results provide novel prognostic molecular markers of early recurrence in PDAC and also suggest that the global epigenetic landscape is a prognostic feature in this disease.
2021-03-31 | GSE124231 | GEO
Project description:About 50% of resected pancreatic ductal adenocarcinoma (PDAC) recur within just one year following surgery. Prognostic molecular markers predicting rapid recurrence are currently unavailable. We hypothesized that epigenetic differences at the level of chromatin accessibility, potentially linked to distinct differentiation states, might distinguish rapidly recurrent from non-recurrent tumors. Therefore, we interrogated genome-wide chromatin accessibility using Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) on EpCAM+ PDAC malignant cells sorted from a cohort of 54 treatment-naïve resected tumors, in hopes of defining a tumor-intrinsic chromatin signature associated with recurrence. We discovered a signature of ~1000 loci that were differentially accessible between recurrent (disease free survival (DFS) < 1 year) and non-recurrent patients (DFS > 1 year). Through transcription factor (TF) binding motif analysis using supervised learning, we identified candidate TFs whose accessible motifs were differentially associated with recurrence. Nuclear localization of two such TFs as selected by top hits, ZKSCAN1 and HNF1b, were assessed by both immunohistochemistry and immunofluorescence on the tissue microarrays (TMA) of 40 out of 54 patients. Nuclear staining of HNF1b was strong in the non-recurrent and weak or absent in the recurrent patients but ZKSCAN1 was not significantly associated with recurrence. In an independent TMA of PDAC cohort (n=97) preselected for 52 long (OS 6 years)- and 45 short (OS 6 months)- term survivors, the number of nuclear positive cells for HNF1b was 52-fold higher in the long-term compared to the short-term survivors and that for ZKSCAN1 was 5.3-fold higher in the short-term compared to the long-term survivors. Altogether, these results provide novel prognostic molecular markers of early recurrence in PDAC and also suggest that the global epigenetic landscape is a prognostic feature in this disease.
2021-03-30 | GSE124230 | GEO