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      Diagnostic and Prognostic Value of SHOX2 and SEPT9 DNA Methylation and Cytology in Benign, Paramalignant and Malignant Pleural Effusions

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          Abstract

          Pleural effusions (PE) are a common clinical problem. The discrimination between benign (BPE), malignant (MPE) and paramalignant (PPE) pleural effusions is highly important to ensure appropriate patient treatment. Today, cytology is the gold standard for diagnosing malignant pleural effusions. However, its sensitivity is limited due to the sometimes low abundance of tumor cells and the challenging assessment of cell morphology in cytological samples. This study aimed to develop and validate a diagnostic test, which allows for the highly specific detection of malignant cells in pleural effusions based on the DNA methylation biomarkers SHOX2 and SEPT9. A quantitative real-time PCR assay was developed which enabled the accurate and sensitive detection of SHOX2 and SEPT9 in PEs. Cytological and DNA methylation analyses were conducted in a case control study comprised of PEs from 114 patients (58 cases, 56 controls). Cytological analysis as well as SHOX2 and SEPT9 methylation resulted in 100% specificity. 21% of the cases were cytologically positive and 26% were SHOX2 or SEPT9 methylation positive. The combined analysis of cytology and DNA methylation resulted in an increase of 71% positively classified PEs from cancer patients as compared to cytological analysis alone. The absolute sensitivity of cytology and DNA methylation was not determinable due to the lack of an appropriate gold standard diagnostic for distinguishing between MPEs and PPEs. Therefore, it was unclear which PEs from cancer patients were malignant (containing tumor cells) and which PEs were paramalignant and resulted from benign conditions in cancer patients, respectively. Furthermore, DNA methylation analysis in PEs allowed the prognosis of the overall survival in cancer patients (Kaplan-Meier analysis, log rank test, p = 0.02 ( SHOX2), p = 0.02 ( SEPT9)). The developed test may be used as a diagnostic and prognostic adjunct to existing clinical and cytopathological investigations in patients with PEs of unclear etiology.

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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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            SHOX2 DNA Methylation is a Biomarker for the diagnosis of lung cancer based on bronchial aspirates

            Bernd Schmidt, Volker Liebenberg, Dimo Dietrich … (2010)
            Background This study aimed to show that SHOX2 DNA methylation is a tumor marker in patients with suspected lung cancer by using bronchial fluid aspirated during bronchoscopy. Such a biomarker would be clinically valuable, especially when, following the first bronchoscopy, a final diagnosis cannot be established by histology or cytology. A test with a low false positive rate can reduce the need for further invasive and costly procedures and ensure early treatment. Methods Marker discovery was carried out by differential methylation hybridization (DMH) and real-time PCR. The real-time PCR based HeavyMethyl technology was used for quantitative analysis of DNA methylation of SHOX2 using bronchial aspirates from two clinical centres in a case-control study. Fresh-frozen and Saccomanno-fixed samples were used to show the tumor marker performance in different sample types of clinical relevance. Results Valid measurements were obtained from a total of 523 patient samples (242 controls, 281 cases). DNA methylation of SHOX2 allowed to distinguish between malignant and benign lung disease, i.e. abscesses, infections, obstructive lung diseases, sarcoidosis, scleroderma, stenoses, at high specificity (68% sensitivity [95% CI 62-73%], 95% specificity [95% CI 91-97%]). Conclusions Hypermethylation of SHOX2 in bronchial aspirates appears to be a clinically useful tumor marker for identifying subjects with lung carcinoma, especially if histological and cytological findings after bronchoscopy are ambiguous.
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              Performance of Epigenetic Markers SEPT9 and ALX4 in Plasma for Detection of Colorectal Precancerous Lesions

              Marc Tänzer, Benjamin Balluff, Jürgen Distler … (2010)
              Background Screening for colorectal cancer (CRC) has shown to reduce cancer-related mortality, however, acceptance and compliance to current programmes are poor. Developing new, more acceptable non-invasive tests for the detection of cancerous and precancerous colorectal lesions would not only allow preselection of individuals for colonoscopy, but may also prevent cancer by removal of precancerous lesions. Methods Plasma from 128 individuals (cohort I – exploratory study: 73 cases / 55 controls ) was used to test the performance of a single marker, SEPT9, using a real-time quantitative PCR assay. To validate performance of SEPT9, plasma of 76 individuals (cohort II – validation study: 54 cases / 22 controls) was assessed. Additionally, improvement of predictive capability considering SEPT9 and additionally ALX4 methylation was investigated within these patients. Results In both cohorts combined, methylation of SEPT9 was observed in 9% of controls (3/33), 29% of patients with colorectal precancerous lesions (27/94) and 73% of colorectal cancer patients (24/33). The presence of both SEPT9 and ALX4 markers was analysed in cohort II and was observed in 5% of controls (1/22) and 37% of patients with polyps (18/49). Interestingly, also 3/5 (60%) patients with colorectal cancer were tested positive by the two marker panel in plasma. Conclusions While these data confirm the detection rate of SEPT9 as a biomarker for colorectal cancer, they also show that methylated DNA from advanced precancerous colorectal lesions can be detected using a panel of two DNA methylation markers, ALX4 and SEPT9. If confirmed in larger studies these data indicate that screening for colorectal precancerous lesions with a blood-based test may be as feasible as screening for invasive cancer.
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                Author and article information

                Contributors
                Goli Samimi: 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: 2013
                Publication date (Electronic): 27 December 2013
                Volume: 8
                Issue: 12
                Electronic Location Identifier: e84225
                Affiliations
                [1 ]University Hospital Bonn (UKB), Institute of Pathology, Bonn, Germany
                [2 ]Metanomics Health GmbH, Berlin, Germany
                [3 ]Roche Pharma AG, Hematology/Oncology, Grenzach-Wyhlen, Germany
                Kinghorn Cancer Centre, Garvan Institute of Medical Research, Australia
                Author notes

                Competing Interests: Claudia Ivascu and Philipp Schatz are employed at Metanomics Health GmbH and Roche Pharma AG, respectively, whose companies funded time on this study. Dimo Dietrich, Claudia Ivascu and Philipp Schatz have been employees and are stockholders of Epigenomics AG, a company that aims to commercialize the DNA methylation markers SEPT9 and SHOX2. Dimo Dietrich and Philipp Schatz are coinventors and own patents on methylation biomarkers and related technologies. Patents: “A Method for Amplification of Nucleic Acids” (WO2006113770), “A Method for the Carry-over Protection in DNA Amplification Systems Targeting Methylation Analysis Achieved by a Modified Pre-treatment of nucleic Acids” (WO2006040187). These patents are commercially exploited by Epigenomics AG. Dimo Dietrich and Philipp Schatz receive inventor's compensation from Epigenomics AG. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: DD MJ PS CI GK. Performed the experiments: MJ SP AL BU SM. Analyzed the data: DD MJ. Wrote the paper: DD MJ EEH GK.

                Article
                Publisher ID: PONE-D-13-31178
                DOI: 10.1371/journal.pone.0084225
                PMC ID: 3874014
                PubMed ID: 24386354
                SO-VID: ebe9b46c-5134-462b-bf2c-ea1c530b6cf4
                Copyright statement: Copyright @ 2013
                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 : 30 July 2013
                Date accepted : 20 November 2013
                Page count
                Pages: 9
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Gene Expression
                Subject: DNA modification
                Subject: Molecular Cell Biology
                Subject: Gene Expression
                Subject: DNA modification
                Subject: Nucleic Acids
                Subject: DNA
                Subject: DNA amplification
                Subject: Medicine
                Subject: Diagnostic Medicine
                Subject: Pathology
                Subject: Clinical Pathology
                Subject: Clinical Chemistry
                Subject: Molecular Genetics
                Subject: Test Evaluation
                Subject: Epidemiology
                Subject: Cancer Epidemiology
                Subject: Molecular Epidemiology
                Subject: Oncology
                Subject: Cancer Detection and Diagnosis

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                ScienceOpen disciplines: Uncategorized

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