Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations
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PROVIDER: EGAS00001003040 | EGA |
REPOSITORIES: EGA
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Project description:MicroRNAs can be used in the prognosis of malignancies; however, their regulatory mechanisms are unknown, especially in pancreatic ductal adenocarcinoma (PDAC).From the 120 PDAC patients who underwent surgical resection, 10 patients with longest survival and 10 with shortest survival were selected. We found that high miR-29b-2-5p expression was associated with good prognosis (p=0.02). The validation cohort confirmed miR-29b-2-5p as an independent prognostic factor in PDAC (n=100, 95%CI=0.305-0.756, p=0.002).
2020-10-25 | GSE106198 | GEO
Project description:Background: Patients with early stage non-small cell lung carcinoma (NSCLC) may benefit from treatments based on more accurate prognosis. A 15-gene prognostic classifier for NSCLC was identified from mRNA expression profiling of tumor samples from the NCIC CTG JBR.10 trial. Here, we assessed its value in an independent set of cases. Methods: Expression profiling was performed on RNA from frozen, resected tumor tissues corresponding to 181 Stage I and II NSCLC cases collected at University Health Network (UHN181). Kaplan-Meier methodology was used to estimate three year overall survival probabilities and the prognostic effect of the classifier was assessed using log-rank testing. Cox proportional hazards model evaluated the signature's effect adjusting for clinical prognostic factors. Results: Expression data of the 15-gene classifier stratified UHN181 cases into high and low-risk subgroups with significantly different overall survival (HR=1.92, 95% CI: 1.15-3.23, p=0.012). Its strength as a prognostic classifier was superior to stage alone (HR=1.52, 95% CI: 0.90-2.55, p-value=0.11). In subgroup analysis, this classifier predicted survival in 127 Stage I patients (HR=2.17, 95% CI: 1.12-4.20, p=0.018) and the smaller subgroup of 48 Stage IA patients (HR=5.61, 95% CI: 1.19-26.45, p=0.014. The signature was prognostic for both adenocarcinoma and squamous cell carcinoma cases (HR= 1.76, p-value=0.058; HR= 4.19, p-value=0.045, respectively). Conclusions: The prognostic accuracy of a 15-gene classifier was validated in an independent cohort of 181 early stage NSCLC samples including Stage IA cases and in different NSCLC histologic subtypes.
2013-12-22 | GSE50081 | GEO
Project description:Background: Patients with early stage non-small cell lung carcinoma (NSCLC) may benefit from treatments based on more accurate prognosis. A 15-gene prognostic classifier for NSCLC was identified from mRNA expression profiling of tumor samples from the NCIC CTG JBR.10 trial. Here, we assessed its value in an independent set of cases. Methods: Expression profiling was performed on RNA from frozen, resected tumor tissues corresponding to 181 Stage I and II NSCLC cases collected at University Health Network (UHN181). Kaplan-Meier methodology was used to estimate three year overall survival probabilities and the prognostic effect of the classifier was assessed using log-rank testing. Cox proportional hazards model evaluated the signature's effect adjusting for clinical prognostic factors. Results: Expression data of the 15-gene classifier stratified UHN181 cases into high and low-risk subgroups with significantly different overall survival (HR=1.92, 95% CI: 1.15-3.23, p=0.012). Its strength as a prognostic classifier was superior to stage alone (HR=1.52, 95% CI: 0.90-2.55, p-value=0.11). In subgroup analysis, this classifier predicted survival in 127 Stage I patients (HR=2.17, 95% CI: 1.12-4.20, p=0.018) and the smaller subgroup of 48 Stage IA patients (HR=5.61, 95% CI: 1.19-26.45, p=0.014. The signature was prognostic for both adenocarcinoma and squamous cell carcinoma cases (HR= 1.76, p-value=0.058; HR= 4.19, p-value=0.045, respectively). Conclusions: The prognostic accuracy of a 15-gene classifier was validated in an independent cohort of 181 early stage NSCLC samples including Stage IA cases and in different NSCLC histologic subtypes. Expression profiling was performed on RNA from frozen, resected tumor tissues corresponding to 181 Stage I and II NSCLC cases collected at University Health Network (UHN181). !Series_contributor = Sandy,D,Der
2013-12-22 | E-GEOD-50081 | biostudies-arrayexpress
Project description:Rationale There is a need for new and better biomarkers for hypertrophic cardiomyopathy (HCM) which correlate more closely with disease progression as determined by clinical imaging and biohumoral information. We have used a combination of heart tissue and plasma proteomics to identify potential biomarkers for HCM and developed them into an exploratory targeted proteomic assay. Objective To identify informative staging biomarkers for HCM and develop them into a blood test. The test using 10 µl of plasma, was developed into a 10 min liquid chromatography-tandem/mass spectrometry (LC-MS/MS) assay to analyze multiple candidate biomarkers and evaluate their association with clinical phenotypes in patients with HCM. Methods and Results Myocardial tissue and plasma samples from patients with HCM and healthy volunteers (controls) were screened using a combined gel- and nano-LC quadrupole time of flight MS approach. Twenty-six potential biomarkers were identified from the proteomics screens and developed into a multiplexed targeted proteomic assay. Their association with clinical phenotypes was tested in plasma samples collected from 207 prospectively recruited participants: 110 patients with HCM (50.1 ± 15.0 years, 70% male; 48 [44%] with identified genetic mutations) and 97 controls (49.6 ± 13.4 years, 58% male), randomly split into training (80 HCM, 67 controls) and validation datasets (30 HCM, 30 controls). Six markers (Aldolase Fructose-Bisphosphate A, Complement C3, Glutathione S-Transferase Omega 1, Ras Suppressor Protein 1, Talin 1, and Thrombospondin 1) were significantly increased (P<0.006) in the plasma of HCM patients compared to controls in the training dataset. These markers correlated with left ventricular (LV) wall thickness, LV mass and % myocardial scar on cardiovascular magnetic resonance imaging. Using supervized machine learning (ML) this panel differentiated HCM from controls (area under the curve: 0.89 in the training dataset, sensitivity 96%, 95% confidence interval [CI] 77–93; specificity 87%, 95%CI 77–94; and 0.87 in the validation dataset, sensitivity 97%, 95%CI 83–100; specificity 77%, 95%CI 58–90). Four of the biomarkers as well as the composite ML score of the plasma proteome correlated with the presence of nonsustained ventricular tachycardia and the estimated 5-year risk of sudden cardiac death. Conclusion By developing a high-throughput, multiplex, and targeted proteomic plasma assay we identified 6 biomarkers that correlate with the presence of disease and with clinical risk score for sudden cardiac death.
2019-07-08 | PXD009859 | Pride
Project description:The sensitivity of conventional techniques for the quantification of minimal/measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is limited to MRD 10-4. Measuring MRD <10-4 could help to further distinguish between CLL patients with durable remission and those at risk of early relapse. We here present a novel, academically developed IGHV leader-based next-generation sequencing (NGS) assay for the quantification of MRD in CLL. We demonstrate, based on measurements in contrived MRD samples, that the linear range of detection and quantification of our novel assay reaches beyond MRD 10-5. If provided with sufficient DNA input, MRD can even be detected down to MRD 10-6. There was high inter-assay concordance between measurements of the IGHV leader-based NGS assay and allele-specific oligonucleotide quantitative PCR (r=0.92, [95%CI 0.86-0.96]) and droplet digital PCR (r=0.93, [95%CI 0.88-0.96]) on contrived MRD samples. In a cohort of 37 patients from the CLL11 trial, using MRD 10-5 as a cut-off, MRD undetectability was associated with superior progression-free survival (PFS) and time to next treatment. Importantly, deeper MRD measurement allowed for additional stratification of patients with MRD <10-4 but ≥10‑5. Whereas the PFS of these patients was significantly shorter, compared to patients with MRD <10-5 (HR 4.9, [95%CI 1.3-17.9], P=0.017), their PFS was superior to those with MRD ≥10‑4 (HR 0.18, [95%CI 0.06-0.46], P<0.001). These results clearly demonstrate the clinical utility of the novel IGHV-leader based NGS assay.
2021-11-13 | GSE188587 | GEO
Project description:Purpose: Renal cell carcinoma (RCC) is often diagnosed incidentally as an early-stage small renal mass (SRM; pT1a, ≤ 4 cm). Increasing concerns surrounding the overtreatment of patients with benign or clinically indolent tumors has led to a shift in current treatment recommendations, especially for elderly and infirm patients. There are currently no available biomarkers to accurately stratify patients according to risk. Therefore, we set out to identify early biomarkers of RCC progression. Experimental Design: We employed label-free LC-MS/MS and targeted parallel-reaction monitoring (PRM) to identify early, non-invasive diagnostic and prognostic biomarkers for early-stage RCC-SRMs. In total, we evaluated 115 urine samples, including 33 renal oncocytoma (≤ 4 cm) cases, 30 progressive and 26 non-progressive clear cell RCC-SRM (ccRCC-SRM) cases, in addition to 26 healthy controls. Results: We identified nine endogenous peptides which displayed significantly elevated expression in ccRCC-SRMs relative to healthy controls. Peptides NVINGGSHAGNKLAMQEF, VNVDEVGGEALGRL, and VVAGVANALAHKYH showed significantly elevated expression in ccRCC-SRMs relative to renal oncocytoma. Additionally, peptides SHTSDSDVPSGVTEVVVKL and IVDNNILFLGKVNRP displayed significantly elevated expression in progressive relative to non-progressive ccRCC-SRMs. Peptide SHTSDSDVPSGVTEVVVKL showed the most significant discriminatory ability (AUC: 0.76, 95% CI: 0.62 to 0.90, p = 0.0027). Patients with elevated SHTSDSDVPSGVTEVVVKL expression had significantly shorter overall survival (HR: 4.13, 95% CI: 1.09 to 15.65, p = 0.024) compared to patients with lower expression. Conclusions: Our in-depth peptidomic analysis identified novel biomarkers for early-stage RCC-SRMs. Characterization of urinary peptides may provide insight into early RCC progression and could potentially help assign patients to appropriate management programs.
2019-08-08 | PXD013111 | Pride
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: In patients with suspicious pulmonary lesions, bronchoscopy is frequently non-diagnostic. This often results in additional invasive testing, including surgical biopsy, although many patients have benign disease. We sought to validate an airway gene-expression classifier for lung cancer in patients undergoing diagnostic bronchoscopy. METHODS: Two multicenter prospective studies (AEGIS 1 and 2) enrolled 1357 current or former smokers undergoing bronchoscopy for suspected lung cancer. Bronchial epithelial cells were collected from normal appearing mucosa in the mainstem bronchus during bronchoscopy. Patients without a definitive diagnosis from bronchoscopy were followed for 12 months. A gene-expression classifier was used to assess the risk of lung cancer, and its performance was evaluated. RESULTS: A total of 298 patients from AEGIS 1 and 341 from AEGIS 2 met criteria for analysis. Bronchoscopy was non-diagnostic for cancer in 272 of 639 patients (43%; 95%CI, 39-46%). The gene expression classifier correctly identified 431 of 487 patients with cancer (89% sensitivity; 95%CI, 85-91%), and 72 of 152 patients without cancer (47% specificity; 95%CI, 40-55%). The combination of the classifier and bronchoscopy had a sensitivity of 97% (95%CI, 95-98%), which was independent of size, location, stage, and histological subtype of lung cancer. In patients with an intermediate pre-test risk (10-60%) of lung cancer, the NPV of the classifier was 91% (95%CI 75-98%). CONCLUSIONS: In patients with an intermediate risk of lung cancer and a non-diagnostic bronchoscopy, a gene-expression classification of “low-risk” warrants consideration of a more conservative diagnostic approach that could reduce unnecessary invasive testing in patients with benign disease.
2015-05-17 | GSE66499 | GEO
Project description:Mutations in the Gα-genes GNAQ and GNA11 are found in 85-90% of uveal melanomas (UMs). We analyzed the association between GNAQ and GNA11 mutations with disease-specific survival, gene expression profiles, and cytogenetic alterations in 219 UMs. Our analysis showed a shorter disease-specific survival of GNA11-mutated cases as compared to those carrying a GNAQ mutation (HR=1.97 [95%CI 1.12-3.46], p=0.02). GNA11 mutated UMs displayed a shorter, but not significant, median months survival of 26.97 [95% CI 25.02-37.08] versus GNAQ patients median months survival of 31.5 [95% CI 30.97-53.51]. The GNA11 mutation was also associated with: i) an increased frequency of loss of BRCA1-associated protein 1 (BAP1) expression (p=0.0005), ii) monosomy of chromosome 3 (p<0.001), iii) amplification of chr8q (p=0.038), iv) the combination of the latter two (p=0.0002), and inversely with v) chr6p gain (p=0.003). We used tandem-affinity-purification and mass spectrometry to show that the two derived G-proteins have different protein interaction partners. Specifically, the Tet Methylcytosine Dioxygenase 2(TET2), a protein that is involved in DNA demethylation, physically interacts with the GNAQ protein but not with GNA11, as confirmed by immunoprecipitation analyses. High-risk UM cases show a clearly different DNA-methylation pattern, suggesting that a different regulation of DNA methylation by the two G-proteins might convey a different risk of progression.
2023-02-27 | GSE197656 | GEO
Project description:Purpose: The purpose of this study was to independently validate two biomarkers, a 44-gene DNA Damage Immune Response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. Materials & Methods: 425 centrally determined TNBC cases from S9313 were identified. DDIR signature was performed on RNA isolated from FFPE tumor tissue (n=381), and samples were classified as DDIR-negative or positive using predefined cutoffs. Evaluation of sTILs was performed as previously described. Markers were tested for prognostic value for disease-free and overall survival (DFS, OS) using Cox regression models adjusted for treatment assignment nodal status and tumor size. Results: Among 425 TNBC patients, median age was 45 years, and 33% were node-positive. DDIR was successfully tested in 90% (381/425) of cases, of which 62% were DDIR signature-positive. DDIR signature positivity was associated with improved DFS (HR=0.67; 95% CI 0.48–0.92, P=0.014) and OS (HR=0.61; 95% CI 0.43–0.89, P=0.009). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR=0.70; 95% CI 0.51–0.96, P=0.028 for sTILs density ≥20% vs. <20%) and OS (HR=0.59; 95% CI 0.41–0.85, P=0.004 for sTILs density ≥20% vs. <20%). The DDIR signature score and sTILs density were moderately correlated (r=0.62) which precluded statistical significance for DFS in a joint model (P=0.08 for DDIR and P=0.25 for sTILs). Conclusion: The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two-thirds of TNBC patients treated with adjuvant AC. DDIR signature has potential to stratify outcome and identify patients with less projected benefit following AC chemotherapy. Clinical trial number: Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment)
2019-09-13 | GSE137356 | GEO