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      Discovery and Validation of New Potential Biomarkers for Early Detection of Colon Cancer

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          Abstract

          Background

          Accurate detection of characteristic proteins secreted by colon cancer tumor cells in biological fluids could serve as a biomarker for the disease. The aim of the present study was to identify and validate new serum biomarkers and demonstrate their potential usefulness for early diagnosis of colon cancer.

          Methods

          The study was organized in three sequential phases: 1) biomarker discovery, 2) technical and biological validation, and 3) proof of concept to test the potential clinical use of selected biomarkers. A prioritized subset of the differentially-expressed genes between tissue types (50 colon mucosa from cancer-free individuals and 100 normal-tumor pairs from colon cancer patients) was validated and further tested in a series of serum samples from 80 colon cancer cases, 23 patients with adenoma and 77 cancer-free controls.

          Results

          In the discovery phase, 505 unique candidate biomarkers were identified, with highly significant results and high capacity to discriminate between the different tissue types. After a subsequent prioritization, all tested genes (N = 23) were successfully validated in tissue, and one of them, COL10A1, showed relevant differences in serum protein levels between controls, patients with adenoma (p = 0.0083) and colon cancer cases (p = 3.2e-6).

          Conclusion

          We present a sequential process for the identification and further validation of biomarkers for early detection of colon cancer that identifies COL10A1 protein levels in serum as a potential diagnostic candidate to detect both adenoma lesions and tumor.

          Impact

          The use of a cheap serum test for colon cancer screening should improve its participation rates and contribute to decrease the burden of this disease.

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          Most cited references36

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          Estimates of cancer incidence and mortality in Europe in 2008.

          J Ferlay, D.M. PARKIN, E Steliarova-Foucher (2010)
          Up-to-date statistics on cancer occurrence and outcome are essential for the planning and evaluation of programmes for cancer control. Since the relevant information for 2008 is not generally available as yet, we used statistical models to estimate incidence and mortality data for 25 cancers in 40 European countries (grouped and individually) in 2008. The calculations are based on published data. If not collected, national rates were estimated from national mortality data and incidence and mortality data provided by local cancer registries of the same or neighbouring country. The estimated 2008 rates were applied to the corresponding country population estimates for 2008 to obtain an estimate of the numbers of cancer cases and deaths in Europe in 2008. There were an estimated 3.2 million new cases of cancer and 1.7 million deaths from cancer in 2008. The most common cancers were colorectal cancers (436,000 cases, 13.6% of the total), breast cancer (421,000, 13.1%), lung cancer (391,000, 12.2%) and prostate cancer (382,000, 11.9%). The most common causes of death from cancer were lung cancer (342,000 deaths, 19.9% of the total), colorectal cancer (212,000 deaths, 12.3%), breast cancer (129,000, 7.5%) and stomach cancer (117,000, 6.8%). Copyright 2009 Elsevier Ltd. All rights reserved.
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            A 'metastasis-prone' signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics.

            Yi Hong, Thomas Downey, Kong Weng Eu … (2010)
            Metastasis is the major cause of cancer mortality. We aimed to find a metastasis-prone signature for early stage mismatch-repair proficient sporadic colorectal cancer (CRC) patients for better prognosis and informed use of adjuvant chemotherapy. The genome-wide expression profiles of 82 age-, ethnicity- and tissue-matched patients and healthy controls were analyzed using the Affymetrix U133 Plus 2 array. Metastasis-negative patients have 5 years or more of follow-up. A 10 x 10 two-level nested cross-validation design was used with several families of classification models to identify the optimal predictor for metastasis. The best classification model yielded a 54 gene-set (74 probe sets) with an estimated prediction accuracy of 71%. The specificity, sensitivity, negative and positive predictive values of the signature are 0.88, 0.58, 0.84 and 0.65, respectively, indicating that the gene-set can improve prognosis for early stage sporadic CRC patients. These 54 genes, including node molecules YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFATC2, and TGM2, integrate multiple bio-functions in various compartments into an intricate molecular network, suggesting that cell-wide perturbations are involved in metastasis transformation. Further, querying the ;Connectivity Map' with a subset (70%) of these genes shows that Gly-His-Lys and securinine could reverse the differential expressions of these genes significantly, suggesting that they have combinatorial therapeutic effect on the metastasis-prone patients. These two perturbagens promote wound-healing, extracellular matrix remodeling and macrophage activation thus highlighting the importance of these pathways in metastasis suppression for early-stage CRC.
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              DNA methylation biomarkers for blood-based colorectal cancer screening.

              Christian Pilarsky, Catherine Lofton-Day, Fabian Model … (2008)
              Sensitive, specific blood-based tests are difficult to develop unless steps are taken to maximize performance characteristics at every stage of marker discovery and development. We describe a sieving strategy for identifying high-performing marker assays that detect colorectal cancer (CRC)-specific methylated DNA in plasma. We first used restriction enzyme-based discovery methods to identify marker candidates with obviously different methylation patterns in CRC tissue and nonpathologic tissue. We then used a selection process incorporating microarrays and/or real-time PCR analysis of tissue samples to further test marker candidates for maximum methylation in CRC tissue and minimum amplification in tissues from both healthy individuals and patients with other diseases. Real-time assays of 3 selected markers were validated with plasma samples from 133 CRC patients and 179 healthy control individuals in the same age range. Restriction enzyme-based testing identified 56 candidate markers. This group was reduced to 6 with microarray and real-time PCR testing. Three markers, TMEFF2, NGFR, and SEPT9, were tested with plasma samples. TMEFF2 methylation was detected in 65% [95% confidence interval, 56%-73%] of plasma samples from CRC patients and not detected in 69% (62%-76%) of the controls. The corresponding results for NGFR were 51% (42%-60%) and 84% (77%-89%); for SEPT9, the values were 69% (60%-77%) and 86% (80%-91%). The stringent criteria applied at all steps of the selection and validation process enabled successful identification and ranking of blood-based marker candidates.
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                Author and article information

                Contributors
                Francisco X. Real: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 12 September 2014
                Volume: 9
                Issue: 9
                Electronic Location Identifier: e106748
                Affiliations
                [1 ]Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO) and CIBERESP, Hospitalet de Llobregat, Barcelona, Spain
                [2 ]Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
                [3 ]Department of Gastroenterology, University Hospital of Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
                [4 ]Department of Pathology, University Hospital of Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
                [5 ]Department of Clinical Sciences, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain
                [6 ]Department of General and Digestive Surgery, Colorectal Unit, University Hospital of Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
                [7 ]Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain
                Centro Nacional de Investigaciones Oncológicas (CNIO), Spain
                Author notes

                Competing Interests: The authors have filed a patent regarding the use of COL10A1 as biomarker for early diagnosis of colon cancer with title: “SERUM BIOMARKER FOR DIAGNOSING COLORECTAL CANCER”. European patent number: EP2680003A1 (28.06.2012) and Spain ES2436667A2(03.01.2014). The authors confirm that this does not alter their adherence to all PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: XS MCB DC VM. Performed the experiments: DO MCB. Analyzed the data: XS MCB DC EG VM. Contributed reagents/materials/analysis tools: XS MCB DC DO VM. Contributed to the writing of the manuscript: XS MCB DC EG RSP VM. Recruitment of patients and collection of clinical data: FRM XSJ JDO RS.

                Article
                Publisher ID: PONE-D-14-18299
                DOI: 10.1371/journal.pone.0106748
                PMC ID: 4162553
                PubMed ID: 25215506
                SO-VID: 4488885c-3d8f-42f1-be1a-1411cd690f62
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 23 April 2014
                Date accepted : 1 August 2014
                Page count
                Pages: 11
                Funding
                This work was supported by the Catalan Institute of Oncology (ICO) and the Private Foundation of the Biomedical Research Institute of Bellvitge (IDIBELL), the Instituto de Salud Carlos III [grants PI08-1635, PI08-1359, PS09-1037, PI11-1439], CIBERESP CB06/02/2005 and the “Acción Transversal del Cancer”, the Catalan Government DURSI [grant 2009SGR1489], the Fundació Privada Olga Torres (FOT), the Spanish Association Against Cancer (AECC) Scientific Foundation, the European Commission [grant FP7-COOP-Health-2007-B HiPerDART], and Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d'Oncología de Catalunya (XBTC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Biochemistry
                Subject: Biomarkers
                Subject: Computational Biology
                Subject: Genome Analysis
                Subject: Transcriptome Analysis
                Subject: Genome Expression Analysis
                Subject: Genetics
                Subject: Cancer Genetics
                Subject: Gene Expression
                Subject: Molecular biology
                Subject: Molecular biology techniques
                Subject: Molecular biology assays and analysis techniques
                Subject: Gene Expression and Vector Techniques
                Subject: Protein Expression
                Subject: Library screening
                Subject: Differential screening using PCR
                Subject: Molecular probe techniques
                Subject: Probe hybridization
                Subject: RNA hybridization
                Subject: Medicine and Health Sciences
                Subject: Epidemiology
                Subject: Biomarker Epidemiology
                Subject: Oncology
                Subject: Cancer Detection and Diagnosis
                Subject: Cancer Screening
                Subject: Cancers and Neoplasms
                Subject: Colorectal Cancer
                Subject: Cancer Prevention
                Subject: Research and Analysis Methods
                Subject: Immunologic Techniques
                Subject: Immunoassays
                Subject: Enzyme-Linked Immunoassays
                Custom metadata
                Data Availability The authors confirm that all data underlying the findings are fully available without restriction. The gene expression dataset is available in the National Center for Biotechnology Information's Gene Expression Omnibus with GEO series accession number GSE44076. All relevant data are within the paper and its Supporting Information files.

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                ScienceOpen disciplines: Uncategorized

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