Epigenetic clonality confers por prognosis in colorrectal cancer patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE81374 | GEO | 2016/08/16
SECONDARY ACCESSION(S): PRJNA321415
REPOSITORIES: GEO
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Project description:In CRC, 1) to identify epigenetic changes at inter-tumor and intra-tumor level, and 2) to relate intra-tumor clonality to clinical, molecular and histopathologic parameters. From 79 FFPE tumors, 3 different regions were macrodissected: invasive front (IF), digestive tract surface (DTS) and central bulk (CB). Clinical, molecular, and histopathologic parameters were stablished. Epigenetic analysis was performed using Infinium 450K beadchip (Illumina) and R statistics. Intra-tumor regions clustered together by patient. The biggest epigenetic changes were in IF vs DTS/CB. By patient, the most often divergent region was IF (49.4%) comparing with DTS and CB (25.3% in both). It did not correlate with histopathologic, molecular and clinical parameters.Epigenetic clonality is higher at intra-tumor level. The highest changes are observed in IF vs DTS/CB. No association with histopathologic, molecular, and clinical characteristics was found. Cohort of CRC patients (N=17) who recieved quemotherapy (FOLFIRI)
2016-08-16 | GSE81472 | GEO
Project description:In CRC, 1) to identify epigenetic changes at inter-tumor and intra-tumor level, and 2) to relate intra-tumor clonality to clinical, molecular and histopathologic parameters. From 79 FFPE tumors, 3 different regions were macrodissected: invasive front (IF), digestive tract surface (DTS) and central bulk (CB). Clinical, molecular, and histopathologic parameters were stablished. Epigenetic analysis was performed using Infinium 450K beadchip (Illumina) and R statistics. Intra-tumor regions clustered together by patient. The biggest epigenetic changes were in IF vs DTS/CB. By patient, the most often divergent region was IF (49.4%) comparing with DTS and CB (25.3% in both). It did not correlate with histopathologic, molecular and clinical parameters.Epigenetic clonality is higher at intra-tumor level. The highest changes are observed in IF vs DTS/CB. No association with histopathologic, molecular, and clinical characteristics was found. Technical replicates of 12 samples previously hybridized on the Infinium HumanMethylation450 to demonstrate technique robustness.
2016-08-16 | GSE81359 | GEO
Project description:In CRC, 1) to identify epigenetic changes at inter-tumor and intra-tumor level, and 2) to relate intra-tumor clonality to clinical, molecular and histopathologic parameters. From 79 FFPE tumors, 3 different regions were macrodissected: invasive front (IF), digestive tract surface (DTS) and central bulk (CB). Clinical, molecular, and histopathologic parameters were stablished. Epigenetic analysis was performed using Infinium 450K beadchip (Illumina) and R statistics. Intra-tumor regions clustered together by patient. The biggest epigenetic changes were in IF vs DTS/CB. By patient, the most often divergent region was IF (49.4%) comparing with DTS and CB (25.3% in both). It did not correlate with histopathologic, molecular and clinical parameters.Epigenetic clonality is higher at intra-tumor level. The highest changes are observed in IF vs DTS/CB. No association with histopathologic, molecular, and clinical characteristics was found.
2016-08-16 | GSE69550 | GEO
Project description:In CRC, 1) to identify epigenetic changes at inter-tumor and intra-tumor level, and 2) to relate intra-tumor clonality to clinical, molecular and histopathologic parameters. From 79 FFPE tumors, 3 different regions were macrodissected: invasive front (IF), digestive tract surface (DTS) and central bulk (CB). Clinical, molecular, and histopathologic parameters were stablished. Epigenetic analysis was performed using Infinium 450K beadchip (Illumina) and R statistics. Intra-tumor regions clustered together by patient. The biggest epigenetic changes were in IF vs DTS/CB. By patient, the most often divergent region was IF (49.4%) comparing with DTS and CB (25.3% in both). It did not correlate with histopathologic, molecular and clinical parameters.Epigenetic clonality is higher at intra-tumor level. The highest changes are observed in IF vs DTS/CB. No association with histopathologic, molecular, and clinical characteristics was found. SNP characterization of 9 patients of teh discovery cohort were hibridized on Infinium HumanOncoArray-500 v1 beadchip, to asses the genetic clonality of the samples among the three intratumoral regions studied.
2016-08-16 | GSE81362 | GEO
Project description:Epigenetic clonality confers por prognosis in colorrectal cancer patients
| PRJNA321415 | ENA
Project description:Colorectal cancer (CRC) is a biologically and clinically heterogeneous disease. Even though many recurrent genomic alterations have been identified that may characterize distinct subgroups, their biological impact and clinical significance as prognostic indicators remain to be defined. The tumor suppressor candidate-3 (TUSC3/N33) locates to a genomic region frequently deleted or silenced in cancers. TUSC3 is a subunit of the oligosaccharyltransferase (OST) complex at the endoplasmic reticulum (ER) which catalyzes bulk N-glycosylation of membrane and secretory proteins. However, the consequences of TUSC3 loss are largely unknown. Thus, the aim of the study was to characterize the functional and clinical relevance of TUSC3 expression in CRC patients' tissues (n=306 cases) and cell lines. TUSC3 mRNA expression was silenced by promoter methylation in 85 % of benign adenomas (n=46 cases) and 35 % of CRCs (n =74 cases). Epidermal growth factor receptor (EGFR) was selected as one exemplary ER-derived target protein of TUSC3-mediated posttranslational modification. We found that TUSC3 inhibited EGFR-signaling and promoted apoptosis in human CRC cells, whereas TUSC3 siRNA knock-down increased EGFR-signaling. Accordingly, in stage I/II node negative CRC patients (n=156 cases) loss of TUSC3 protein expression was associated with poor overall survival. In sum, our data suggested that epigenetic silencing of TUSC3 may be useful as a molecular marker for progression of early CRC.
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Project description:Depletion of POLQ (DNA polymerase theta) has recently been shown to render tumour cells more sensitive to radiotherapy whilst having little or no effect on normal tissues. This finding led us to investigate whether tumours that overexpress POLQ are associated with an adverse outcome. We therefore correlated the clinical outcomes of two retrospective series of patients with early breast cancer with the expression levels of POLQ, as determined by microarray gene expression analysis. We found that a significant number of tumours overexpressed POLQ and that overexpression was correlated with ER negative disease (p=0.047) and high tumour grade (p=0.004), both of which are associated with poor clinical outcomes. POLQ overexpression was associated with poor relapse free survival rates on both univariate (HR 5.80; 95% CI, 2.220 to 15.159; p<0.001) and multivariate analysis (HR 8.086; 95% CI 2.340 to 27.948 p=0.001). Analysis of other published clinical series confirmed that POLQ overexpression is associated with adverse clinical outcomes. The poor prognosis associated with POLQ is independent of other clinical or pathological features. The mechanism that causes this adverse outcome remains to be elucidated but may in part arise from resistance to adjuvant treatment. These findings, combined with the limited normal tissue expression of POLQ, make it a very appealing target for possible clinical exploitation.
| S-EPMC2917771 | biostudies-literature
Project description:BackgroundEpigenetics studies heritable or inheritable mechanisms that regulate gene expression rather than altering the DNA sequence. However, no research has investigated the link between TME-related genes (TRGs) and epigenetic-related genes (ERGs) in GC.MethodsA complete review of genomic data was performed to investigate the relationship between the epigenesis tumor microenvironment (TME) and machine learning algorithms in GC.ResultsFirstly, TME-related differential expression of genes (DEGs) performed non-negative matrix factorization (NMF) clustering analysis and determined two clusters (C1 and C2). Then, Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) rates suggested that cluster C1 predicted a poorer prognosis. The Cox-LASSO regression analysis identified eight hub genes (SRMS, MET, OLFML2B, KIF24, CLDN9, RNF43, NETO2, and PRSS21) to build the TRG prognostic model and nine hub genes (TMPO, SLC25A15, SCRG1, ISL1, SOD3, GAD1, LOXL4, AKR1C2, and MAGEA3) to build the ERG prognostic model. Additionally, the signature's area under curve (AUC) values, survival rates, C-index scores, and mean squared error (RMS) curves were evaluated against those of previously published signatures, which revealed that the signature identified in this study performed comparably. Meanwhile, based on the IMvigor210 cohort, a statistically significant difference in OS between immunotherapy and risk scores was observed. It was followed by LASSO regression analysis which identified 17 key DEGs and a support vector machine (SVM) model identified 40 significant DEGs, and based on the Venn diagram, eight co-expression genes (ENPP6, VMP1, LY6E, SHISA6, TMEM158, SYT4, IL11, and KLK8) were discovered.ConclusionThe study identified some hub genes that could be useful in predicting prognosis and management in GC.
| S-EPMC10216680 | biostudies-literature
Project description:BackgroundGastric cancer at different locations has distinct prognoses and biological behaviors, but the specific mechanism is unclear.MethodsNon-targeted metabolomics was performed to examine the differential metabolite phenotypes that may be associated with the effects of tumor location on the prognosis of gastric cancer. And silencing of the rate-limiting enzyme to evaluate the effect of abnormal changes in metabolic pathway on the functional biological assays of gastric cancer cells HGC-27 and MKN28.ResultsIn a retrospective study of 94 gastric cancer patients, the average survival time of patients with gastric cancer in the middle third of the stomach was significantly lower than that of patients with gastric cancer in other locations (p < 0.05). The middle third location was also found to be an independent risk factor for poor prognosis (HR = 2.723, 95%CI 1.334-5.520), which was closely associated with larger tumors in this location. Non-targeted metabolomic analysis showed that the differential metabolites affected 16 signaling pathways including arginine synthesis, retrograde endocannabinoid signaling, arginine biosynthesis, and alanine and aspartate and glutamate metabolism between gastric cancer and normal tissue, as well as between tumors located in the middle third of the stomach and other locations. Argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme of the arginine biosynthesis pathway, catalyzes the production of argininosuccinic acid. Here, knockdown of ASS1 significantly inhibited the proliferation, colony formation, and migration/invasion of gastric cancer cells, and promoted apoptosis.ConclusionsOur study suggests that abnormal arginine synthesis may lead to larger tumor size and worse prognosis in gastric cancer located in the middle third position of the stomach. These findings may provide the basis for the stratification and targeted treatment of gastric cancer in different locations.
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Project description:Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer.
2019-07-09 | GSE123754 | GEO