scholarly journals Gel-Based Proteomics of Clinical Samples Identifies Potential Serological Biomarkers for Early Detection of Colorectal Cancer

2019 ◽  
Vol 20 (23) ◽  
pp. 6082 ◽  
Author(s):  
Stine Thorsen ◽  
Irina Gromova ◽  
Ib Christensen ◽  
Simon Fredriksson ◽  
Claus Andersen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Detection ◽  
Biomarker Discovery ◽  
Real Life ◽  
Clinical Samples ◽  
Plasma Samples ◽  
Healthy Individuals ◽  
Protein Biomarkers ◽  
2D Gel ◽  
Cancer Diseases

The burden of colorectal cancer (CRC) is considerable—approximately 1.8 million people are diagnosed each year with CRC and of these about half will succumb to the disease. In the case of CRC, there is strong evidence that an early diagnosis leads to a better prognosis, with metastatic CRC having a 5-year survival that is only slightly greater than 10% compared with up to 90% for stage I CRC. Clearly, biomarkers for the early detection of CRC would have a major clinical impact. We implemented a coherent gel-based proteomics biomarker discovery platform for the identification of clinically useful biomarkers for the early detection of CRC. Potential protein biomarkers were identified by a 2D gel-based analysis of a cohort composed of 128 CRC and site-matched normal tissue biopsies. Potential biomarkers were prioritized and assays to quantitatively measure plasma expression of the candidate biomarkers were developed. Those biomarkers that fulfilled the preset criteria for technical validity were validated in a case-control set of plasma samples, including 70 patients with CRC, adenomas, or non-cancer diseases and healthy individuals in each group. We identified 63 consistently upregulated polypeptides (factor of four-fold or more) in our proteomics analysis. We selected 10 out of these 63 upregulated polypeptides, and established assays to measure the concentration of each one of the ten biomarkers in plasma samples. Biomarker levels were analyzed in plasma samples from healthy individuals, individuals with adenomas, CRC patients, and patients with non-cancer diseases and we identified one protein, tropomyosin 3 (Tpm3) that could discriminate CRC at a significant level (p = 0.0146). Our results suggest that at least one of the identified proteins, Tpm3, could be used as a biomarker in the early detection of CRC, and further studies should provide unequivocal evidence for the real-life clinical validity and usefulness of Tpm3.

DNA methylation profiling from circulating tumor DNA for early-detection of colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15076-e15076
Author(s):  
Wei Zhang ◽  
Jinke Sui ◽  
Xianrui Wu ◽  
Fuao Cao ◽  
Guanyu Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Early Detection ◽  
Methylation Status ◽  
Stage I ◽  
Support Vector ◽  
Plasma Samples ◽  
Neoplastic Progression ◽  
Healthy Individuals ◽  
Early Stage Disease

e15076 Background: Colorectal cancer (CRC) develops as a result of neoplastic progression, which often takes decades, providing a window for early detection. Unfortunately, there has been little success in developing blood-based screening method due to the low amount of ctDNA present in the circulation, especially in patients with early stage disease. The role of aberrant DNA methylation, occurring very early in tumorigenesis, has been well elucidated. In this prospective study, we evaluated the potentiality of DNA methylation status obtained from ctDNA as an early detection method. Methods: Panel Design: Methylation data of tumor samples (12 types, n = 4,772), adjacent normal (8 types, n = 411), and normal white blood cells (n = 656) from TCGA and GSE were compared. Differentially methylated sites were extracted using modified wald-test with an adjusted p-value < 0.05 and fold-change > 2. Our panel covers 80,672 CpG sites, spanning 1.05Mb of human genome. We performed targeted bisulfite sequencing on plasma samples of 67 (stage I: 13, II:29, III: 23, IV: 2) Chinese CRC patients and 144 healthy individuals to construct a model for deriving markers that are differentially methylated and their associated weight. The model was validated in 2 independent cohorts. Results: We constructed a model using a support vector machine (SVM)-based machine learning classifier based on top 4,000 differentially methylated regions (DMRs) selected by random forest between tumor and normal plasma samples. Subsequently, 5-fold cross-validation with 100-time repeats were performed to gain a robust estimation of model performance, achieving a sensitivity of 91%, specificity of 98% and area under curve (AUC) of 98.6%. The model was subsequently validated in 2 independent cohorts: one consisted of 57 stage I-III CRC patients and 74 healthy individuals and another one with 47 stage IV patients and the same 74 healthy individuals. The model yielded a sensitivity of 83% and 95% for the early and late stage cohorts, respectively. A specificity of 95% was obtained for both cohorts. Conclusions: Our findings demonstrated the potential of profiling DNA methylation, which can effectively distinguish cancerous from healthy, for the purpose of screening. This method has potential to serve as a supplementary or alternative approach in early detection.

Proteomic analysis for early detection of ovarian cancer: A realistic approach?

2003 ◽  
Vol 13 (Suppl 2) ◽  
pp. 133-139 ◽  
Author(s):  
E. V. Stevens ◽  
L. A. Liotta ◽  
E. C. Kohn
Keyword(s):  
Ovarian Cancer ◽  
Early Detection ◽  
Serum Protein ◽  
Mass Spectroscopy ◽  
Biomarker Discovery ◽  
Protein Pattern ◽  
Protein Biomarkers ◽  
Promising Tool ◽  
Chip Technology ◽  
Stage Disease

Ovarian cancer is a multifaceted disease wherein most women are diagnosed with advanced stage disease. One of the most imperative issues in ovarian cancer is early detection. Biomarkers that allow cancer detection at stage I, a time when the disease is amenable to surgical and chemotherapeutic cure in over 90% of patients, can dramatically alter the horizon for women with this disease. Recent developments in mass spectroscopy and protein chip technology coupled with bioinformatics have been applied to biomarker discovery. The complexity of the proteome is a rich resource from which the patterns can be gleaned; the pattern rather than its component parts is the diagnostic. Serum is a key source of putative protein biomarkers, and, by its nature, can reflect organ-confined events. Pioneering use of mass spectroscopy coupled with bioinformatics has been demonstrated as being capable of distinguishing serum protein pattern signatures of ovarian cancer in patients with early- and late-stage disease. This is a sensitive, precise, and promising tool for which further validation is needed to confirm that ovarian cancer serum protein signature patterns can be a robust biomarker approach for ovarian cancer diagnosis, yielding improved patient outcome and reducing the death and suffering from ovarian cancer.

MicroRNA in biofluids—Robust biomarkers for disease, toxicology, or injury studies: The case of minimally invasive colorectal cancer detection.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 20-20
Author(s):  
Peter Mouritzen ◽  
Søren Jensby Nielsen ◽  
Maria Wrang Teilum ◽  
Thorarinn Blondal ◽  
Ditte Andreasen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Detection ◽  
Biomarker Discovery ◽  
Expression Profiles ◽  
Minimal Invasive ◽  
Reference Ranges ◽  
Disease States ◽  
A Genome ◽  
New Biomarkers ◽  
Clinical Source

20 Background: MicroRNAs function as post-transcriptional regulators of gene expression. Their high relative stability in common clinical source materials (FFPE blocks, plasma, serum, urine, saliva, etc.) and the ability of microRNA expression profiles to accurately classify discrete tissue types and specific disease states have positioned microRNAs as promising new biomarkers for diagnostic application. Furthermore microRNAs have been shown to be rapidly released from tissues into the circulation with the development of pathology. Methods: Thousands of biofluid samples were profiled including blood derived plasma/serum and urine using a genome-wide LNA-based microRNA qPCR platform, which has unparalleled sensitivity and robustness even in biofluids with extremely low microRNA levels. Only a single RT reaction is required to conduct full miRNome profiling thereby facilitating high-throughput profiling without the need for pre-amplification. Results: Normal reference ranges for circulating microRNAs were determined in several biofluids, allowing development of qPCR arrays containing only relevant microRNA subsets present in various biofluids together with tissue specific microRNA markers. Procedures were developed to control pre-analytical variables, for quality checking and qualifying biofluid samples in particular serum and plasma but also urine and other biofluids. An extensive QC system was implemented in order to secure technical excellence and reveal any unwanted bias in the dataset. We currently screen and validate microRNAs biomarkers for cancer with the aim of developing minimal invasive tests to be applied in early detection population screens. Conclusions: The qPCR panels support development of robust biomarkers in disease, toxicology, and injury studies. We will demonstrate how panels may be quickly and robustly applied in biomarker discovery/validation projects using the specific case early detection of colorectal cancer in blood. Close attention is required on pre-analytical parameters. Hemolysis and cellular contamination affect miRNA profiles in biofluids and control is required.

Head-to-Head Comparison and Evaluation of 92 Plasma Protein Biomarkers for Early Detection of Colorectal Cancer in a True Screening Setting

2015 ◽  
Vol 21 (14) ◽  
pp. 3318-3326 ◽  
Author(s):  
Hongda Chen ◽  
Manuela Zucknick ◽  
Simone Werner ◽  
Phillip Knebel ◽  
Hermann Brenner
Keyword(s):  
Colorectal Cancer ◽  
Early Detection ◽  
Plasma Protein ◽  
Protein Biomarkers

scholarly journals Plasma-derived exosomal miR-15a-5p as a promising diagnostic biomarker for early detection of endometrial carcinoma

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Lanyun Zhou ◽  
Wei Wang ◽  
Fenfen Wang ◽  
Siqi Yang ◽  
Jiaqi Hu ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Early Detection ◽  
Healthy Subjects ◽  
Biomarker Discovery ◽  
Clinical Manifestations ◽  
Reproductive Hormones ◽  
Small Rna Sequencing ◽  
Plasma Samples ◽  
Diagnostic Biomarker ◽  
Auc Value

AbstractEndometrial cancer (EC) is a major cause of death among gynecologic malignancies. To improve early detection of EC in patients, we carried out a large plasma-derived exosomal microRNA (miRNA) studies for diagnostic biomarker discovery in EC. Small RNA sequencing was performed to identify candidate exosomal miRNAs as diagnostic biomarkers in 56 plasma samples from healthy subjects and EC patients. These miRNA candidates were further validated in 202 independent plasma samples by droplet digital PCR (ddPCR), 32 pairs of endometrial tumors and adjacent normal tissues by quantitative real-time PCR (qRT-PCR), and matched plasma samples of 12 patients before and after surgery by ddPCR. miR-15a-5p, miR-106b-5p, and miR107 were significantly upregulated in exomes isolated from plasma samples of EC patients compared with healthy subjects. Particularly, miR-15a-5p alone yielded an AUC value of 0.813 to distinguish EC patients with stage I from healthy subjects. The integration of miR-15a-5p and serum tumor markers (CEA and CA125) achieved a higher AUC value of 0.899. There was also a close connection between miR-15a-5p and clinical manifestations in EC patients. Its exosomal expression was not only associated with the depth of muscular infiltration and aggressiveness of EC, but also correlated with levels of reproductive hormones such as TTE and DHEAS. Collectively, plasma-derived exosomal miR-15a-5p is a promising and effective diagnostic biomarker for the early detection of endometrial cancer.

scholarly journals Multiplex screening of 275 plasma protein biomarkers to identify a signature for early detection of colorectal cancer

2019 ◽  
Vol 14 (1) ◽  
pp. 8-21 ◽  
Author(s):  
Megha Bhardwaj ◽  
Korbinian Weigl ◽  
Kaja Tikk ◽  
Axel Benner ◽  
Petra Schrotz‐King ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Detection ◽  
Plasma Protein ◽  
Protein Biomarkers

scholarly journals A Hypothesis-Directed Approach to the Targeted Development of a Multiplexed Proteomic Biomarker Assay for Cancer

2015 ◽  
Vol 14 ◽  
pp. CIN.S24388 ◽  
Author(s):  
Emily M. Mackay ◽  
Jennifer Koppel ◽  
Pooja Das ◽  
Joanna Woo ◽  
David C. Schriemer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Detection ◽  
Diagnostic Test ◽  
Clinical Setting ◽  
Ranking Method ◽  
Clinical Validation ◽  
Protein Biomarkers ◽  
Clinical Applicability ◽  
Candidate Protein ◽  
Selection Of

In recent years, hundreds of candidate protein biomarkers have been identified using discovery-based proteomics. Despite the large number of candidate biomarkers, few proteins advance to clinical validation. We propose a hypothesis-driven approach to identify candidate biomarkers, previously characterized in the literature, with the highest probability of clinical applicability. A ranking method, called the “hypothesis-directed biomarker ranking” (HDBR) system, was developed to score candidate biomarkers based on seven criteria deemed important in the selection of clinically useful biomarkers. To demonstrate its application, we applied the HDBR system to identify candidate biomarkers for the development of a diagnostic test for the early detection of colorectal cancer. One-hundred and fifty-one candidate biomarkers were identified from the literature and ranked based on the specified criteria. The top-ranked candidates represent a group of biomarkers whose further study and validation would be justified in order to expedite the development of biomarkers that could be used in a clinical setting.

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