Transcripts related to lung cancer disease in blood samples obtained from diagnostic and pre-diagnostic cohorts
Ontology highlight
ABSTRACT: Lung cancer (LC) mortality rates are still increasing globally. As survival is linked to stage, there is a need to identify markers for earlier LC diagnosis and individualized treatment. The circulating transcriptome of LC patients represents a source of potential LC biomarkers. We used genome-wide RNA sequencing to identify LC candidate markers by comparing expression of >60,000 genes in whole blood specimens taken at LC diagnosis from cases (n=128) and controls (n=62). Further, we evaluated expression of these markers in two population-based studies with pre-diagnostic whole blood specimens taken up to eight years prior to LC diagnosis (n=163 cases, 184 matched controls). We identified 14 candidate genes in whole blood associated with LC at diagnosis. High expression of ANXA3, ARG1 and HP was strongly associated with lower survival in late-stage LC cases (adjusted p-values 0.009, 0.03, and 0.007, respectively). We observed strong association of ANXA3 and ARG1 expression with LC also in the pre-diagnostic blood specimens, and especially with late-stage LC within two years of diagnosis (odds ratios 3.47 and 5.00, respectively). Although blood neutrophils were elevated in LC cases both in the diagnostic and pre-diagnostic blood specimens, the observed associations of ANXA3, ARG1 and HP with LC were preserved also after adjusting for elevated blood neutrophils. Our results indicate that in whole blood, increased expression levels of ANXA3, ARG1 and HP are diagnostic and prognostic markers of late-stage LC.
Project description:Altered levels of microRNAs (miRNAs) in blood may contribute to identification of individuals with lung cancer (LC) but may also be early systemic signals of increased LC risk. We compared expression of 1663 miRNAs in blood collected during diagnostic workup for confirmed LC cases (n=128) to that in individuals with suspected but confirmed negative LC (n=62) and identified nine candidate miRNAs upregulated in LC cases. Higher expression of three candidates, miR-320b, 320c, and 320d, was associated with poor survival, independent of LC stage and subtype. To investigate pre-diagnostic profiles of the candidate miRNAs, we assessed their blood expression up to eight years prior to LC diagnosis in population-based cohorts compared to matched controls (n=360 cases, 375 controls). Expression of miR-320c and miR-320d was higher especially in cases sampled within two years prior to LC diagnosis. Thus, elevated levels of miR-320c and miR-320d may be early indications of severe LC.
Project description:Background: Lung cancer (LC) is the leading cause of cancer deaths worldwide with more than 1.7 million deaths each year. Early detection of LC may be crucial to achieve efficient treatment and to increase survival. However, there are limitations to current methods for early detection of LC as they are too invasive and represent potential health hazards, necessitating improved tools to detect LC at an early stage. Blood-based gene expression profiling is an alternative, or additional tool for diagnostic purposes as blood samples are easily available, essentially non-invasive, and can be collected at a low cost. However, as the blood collection method can affect measured gene expression, the aim of this study was to identify mRNAs that are robust biomarkers for LC in blood. How: We sampled blood from 123 LC patients at the St. Olavs university hospital, and 180 controls from two different biobanks sampled on two different blood tubes (PAXgene and Tempus) and used Illumina (HT-12 v4) microarrays to measure whole blood gene expression. We did three analyses: (i) finding relevant gene expression differences between cases and controls, (ii) finding a robust set of genes to be used as a panel to identify presence of LC in blood, and (iii) identifying differences between patients with different pathological traits such as stage and histology. We collected phenotype data from questionnaires and hospital medical records, and evaluated the potential effects of CRP, tumour size, gender, and smoking habits. Results: By comparing cases and controls sampled on the same RNA sampling system (training set), we identified 355 significant genes (Bonferroni adjusted p < 0.05) with biological relevance. When evaluating these on our test set comprising of the same cases as used in the training set but analysed against controls from a different biobank sampled on a different RNA sampling system (test set), we found 50 genes that were robust as they were unaffected by either technical issues in sampling systems, biobank differences, gender, or pathological traits such as LC subtype or stadium. These findings were confirmed in three validation sets and the robust list’s diagnostic potential was validated on RNA sequencing data from a new cohort. By analysing the cases separately, we found seven genes distinguishing squamous cell carcinoma (SCC) from other LC subtypes, and six genes distinguishing early from late-stage LC patients. Pathway analyses and a literature survey indicated that the identified genes show biological relevance for cancer development and lung related diseases.
Project description:The paper "Metabolomic Machine Learning Predictor for Diagnosis and Prognosis of Gastric Cancer" addresses the need for non-invasive diagnostic tools for gastric cancer (GC). Traditional methods like endoscopy are invasive and expensive. The authors conducted a targeted metabolomics analysis of 702 plasma samples to develop machine learning models for GC diagnosis and prognosis. The diagnostic model, using 10 metabolites, achieved a sensitivity of 0.905, outperforming conventional protein marker-based methods. The prognostic model effectively stratified patients into risk groups, surpassing traditional clinical models.
I have successfully reproduced the diagnosis model from the paper. This machine learning-based system differentiates GC patients from non-GC controls using metabolomics data from plasma samples analyzed by liquid chromatography-mass spectrometry (LC-MS). The model focuses on 10 metabolites, including succinate, uridine, lactate, and serotonin. Employing LASSO regression and a random forest classifier, the model achieved an AUROC of 0.967, with a sensitivity of 0.854 and specificity of 0.926. This model significantly outperforms traditional diagnostic methods and underscores the potential of integrating machine learning with metabolomics for early GC detection and treatment.
Project description:To develop diagnostic and prognostic biomarkers, we compared methylation profiles of HCC tissues and normal blood by analyzing 485,000 CpG markers and identified a HCC enriched methylation marker panel compared to that of normal blood. We found there was a highly correlation of methylation profiles between DNA from HCC cancer tissue and matched plasma ctDNA within the same patient. We then selected 10 markers from this panel and created a combined diagnosis score (cd-score) which showed high diagnostic specificity and sensitivity in both a training cohort and an independent validation cohort. We also showed the cd-score correlate highly with tumor load, treatment response and stage and is superior to that by AFP. We also showed the cd-score correlate highly with tumor load, treatment response and stage and is superior to that by AFP. Additional, we generated 8 markers from unicox and LASSO-cox analysis and created a combined prognosis score (cp-score) which could predict prognosis and survival. Together, these findings demonstrated the utility of ctDNA methylation markers in the diagnosis, treatment evaluation and prognosis of HCC.
Project description:Bronchoscopy is a frequently used initial diagnostic procedure for patients with suspected lung cancer (LC). Cytological examinations of bronchial washing (BW) samples obtained during bronchoscopy often yield inconclusive results regarding LC diagnosis. The present study aimed to identify molecular biomarkers as a non-invasive method for LC diagnosis. Aberrant DNA methylation is used as a useful biomarker for LC. Therefore, microarray-based methylation profiling analyses on 13 patient-matched tumor tissues at stages I-III vs. non-tumor tissues were performed, and a group of highly differentially methylated genes was identified. A subsequent analysis using bisulfite-pyrosequencing with additional tissues and cell lines revealed six methylated genes [ADAM metallopeptidase with thrombospondin type 1 motif 20, forkhead box C2 (mesenchyme forkhead 1), NK2 transcription factor related, locus 5 (Drosophila), oligodendrocyte transcription factor 3, protocadherin γ subfamily A 12 (PCDHGA12) and paired related homeobox 1 (PRRX1)] associated with LC. Next, a highly sensitive and accurate detection method, linear target enrichment-quantitative methylation-specific PCR in a single closed tube, was applied for clinical validation using BW samples from patients with LC (n=68) and individuals with benign diseases (n=33). PCDHGA12 and PRRX1 methylation were identified as the best-performing biomarkers to detect LC. The two-marker combination showed a sensitivity of 82.4% and a specificity of 87.9%, with an area under the curve of 0.891. Notably, the sensitivity for small cell LC was 100%. The two-marker combination had a positive predictive value of 93.3% and a negative predictive value of 70.7%. The sensitivity was higher than that of cytology, which only had a sensitivity of 50%. The methylation status of the two-marker combination showed no association with sex, age or stage, but was associated with tumor location and histology. In conclusion, the present study showed that the regulatory regions of PCDHGA12 and PRRX1 are highly methylated in LC and can be used to detect LC in BW specimens as a diagnostic adjunct to cytology in clinical practice.
Project description:Background
There is a need for diagnostic tests for screening, triaging and staging of epithelial ovarian cancer (EOC). Glycoproteomics of blood samples has shown promise for biomarker discovery.
Methods
We applied glycoproteomics to serum of people with EOC or benign pelvic masses and healthy controls. A total of 653 analytes were quantified and assessed in multivariable models, which were tested in an independent cohort. Additionally, we analyzed glycosylation patterns in serum markers and in tissues.
Results
We identified a biomarker panel that distinguished benign lesions from EOC with sensitivity and specificity of 83.5% and 90.1% in the training set, and of 86.7 and 86.7% in the test set, respectively. ROC analysis demonstrated strong performance across a range of cutoffs. Fucosylated multi-antennary glycopeptide markers were higher in late-stage than in early-stage EOC. A comparable pattern was found in late-stage EOC tissues.
Conclusions
Blood glycopeptide biomarkers have the potential to distinguish benign from malignant pelvic masses, and early- from late-stage EOC. Glycosylation of circulating and tumor tissue proteins may be related. This study supports the hypothesis that blood glycoproteomic profiling can be used for EOC diagnosis and staging and it warrants further clinical evaluation.
Project description:Genome wide DNA methylation profiling of blood samples collected from patients after diagnosis with hepatocellular carcinoma (HCC) (cases) vs. blood samples collected from healthy individuals without family history of cancer (controls). The Illumina Infinium 450K Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 450,000 CpGs in human samples corresponding to cases (post-diagnostic HCC) and controls. Samples included 24 cases and 24 controls. Cases were matched with controls on gender, age, ethnicity, hepatitis C infection, and diabetes. The presence or absence of HCC in our study was determined based on the AASLD criteria.
Project description:Genome wide DNA methylation profiling of blood samples collected from patients prior to diagnosis with hepatocellular carcinoma (HCC) vs. blood samples collected from healthy individuals without family history of cancer. The Illumina Infinium 450K Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 450,000 CpGs in human samples corresponding to cases (pre-diagnostic HCC) and controls. Samples included 21 cases and 21 controls. Cases were matched with controls on gender, age, ethnicity, hepatitis C infection, and diabetes. The presence or absence of HCC in our study was determined based on the AASLD criteria.
Project description:To identify early biomarkers at the precancerous stage of cholangiocarcinoma through serum proteomics and validate key proteins as potential diagnostic markers
Project description:Background: Human African trypanosomiasis (HAT), also called sleeping sickness, is one of 20 in WHO’s list of ‘Neglected Tropical Diseases’, for which, less than 3,500 cases are reported each year. The disease is caused by the parasite Trypanosoma brucei. Even though the clinical symptoms are well described, physiological aspects of the disease remain unclear. Diagnosis of the disease is difficult, requiring a lumbar puncture to determine the disease stage and guide treatment. Identifying new markers for disease stage has been a challenge for many years. Methods and Findings: In our study, a liquid chromatography coupled with tandem mass spectrometry tandem approach (LC-MS/MS) provides a new way to establish the proteomic profile of patients in stages 1 and 2 of the disease. The biological fluids (serum, cerebrospinal fluid, urine and saliva) of three uninfected controls, three patients with stage 1 disease, and four patients with stage 2 disease, are analyzed. In addition, quantification of samples from 14 controls, 23 patients with stage 1 disease and 43 patients with stage 2 disease by ELISA completes this analysis, and highlights two potential new markers, neuroserpin and moesin, with the latter present in urine — an easily accessed fluid. Conclusion: These result suggest that quantifying proteins present in biological fluids by LC-MS/MS) could provide new biomarkers for the diagnosis and stage discrimination of HAT.