Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay

Robert Grützmann, B. Molnár, Christian Pilarsky, Jens K. Habermann, Peter M. Schlag, Hans D. Saeger, Stephan Miehlke, Thomas Stolz, Fabian Model, Uwe J. Roblick, Hans Peter Bruch, Rainer Koch, Volker Liebenberg, Theo deVos, Xiaoling Song, Robert H. Day, Andrew Z. Sledziewski, Catherine Lofton-Day

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Abstract

Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths despite the fact that detection of this cancer in early stages results in over 90% survival rate. Currently less than 45% of at-risk individuals in the US are screened regularly, exposing a need for better screening tests. We performed two case-control studies to validate a blood-based test that identifies methylated DNA in plasma from all stages of CRC. Methodology/Principal Findings: Using a PCR assay for analysis of Septin 9 (SEPT9) hypermethylation in DNA extracted from plasma, clinical performance was optimized on 354 samples (252 CRC, 102 controls) and validated in a blinded, independent study of 309 samples (126 CRC, 183 controls). 168 polyps and 411 additional disease controls were also evaluated. Based on the training study SEPT9-based classification detected 120/252 CRCs (48%) and 7/102 controls (7%). In the test study 73/126 CRCs (58%) and 18/183 control samples (10%) were positive for SEPT9 validating the training set results. Inclusion of an additional measurement replicate increased the sensitivity of the assay in the testing set to 72% (90/125 CRCs detected) while maintaining 90% specificity (19/183 for controls). Positive rates for plasmas from the other cancers (11/96) and non-cancerous conditions (41/315) were low. The rate of polyp detection (>1 cm) was ∼20%. Conclusions/Significance: Analysis of SEPT9 DNA methylation in plasma represents a straightforward, minimally invasive method to detect all stages of CRC with potential to satisfy unmet needs for increased compliance in the screening population. Further clinical testing is warranted.

Original languageEnglish
Article numbere3759
JournalPLoS One
Volume3
Issue number11
DOIs
Publication statusPublished - Nov 19 2008

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Septins
DNA methylation
DNA Methylation
colorectal neoplasms
Colorectal Neoplasms
Assays
Blood
blood
assays
Plasmas
Polyps
neoplasms
testing
Screening
screening
risk groups
Disease control
DNA
Hematologic Tests
case-control studies

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Grützmann, R., Molnár, B., Pilarsky, C., Habermann, J. K., Schlag, P. M., Saeger, H. D., ... Lofton-Day, C. (2008). Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. PLoS One, 3(11), [e3759]. https://doi.org/10.1371/journal.pone.0003759

Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. / Grützmann, Robert; Molnár, B.; Pilarsky, Christian; Habermann, Jens K.; Schlag, Peter M.; Saeger, Hans D.; Miehlke, Stephan; Stolz, Thomas; Model, Fabian; Roblick, Uwe J.; Bruch, Hans Peter; Koch, Rainer; Liebenberg, Volker; deVos, Theo; Song, Xiaoling; Day, Robert H.; Sledziewski, Andrew Z.; Lofton-Day, Catherine.

In: PLoS One, Vol. 3, No. 11, e3759, 19.11.2008.

Research output: Contribution to journalArticle

Grützmann, R, Molnár, B, Pilarsky, C, Habermann, JK, Schlag, PM, Saeger, HD, Miehlke, S, Stolz, T, Model, F, Roblick, UJ, Bruch, HP, Koch, R, Liebenberg, V, deVos, T, Song, X, Day, RH, Sledziewski, AZ & Lofton-Day, C 2008, 'Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay', PLoS One, vol. 3, no. 11, e3759. https://doi.org/10.1371/journal.pone.0003759
Grützmann, Robert ; Molnár, B. ; Pilarsky, Christian ; Habermann, Jens K. ; Schlag, Peter M. ; Saeger, Hans D. ; Miehlke, Stephan ; Stolz, Thomas ; Model, Fabian ; Roblick, Uwe J. ; Bruch, Hans Peter ; Koch, Rainer ; Liebenberg, Volker ; deVos, Theo ; Song, Xiaoling ; Day, Robert H. ; Sledziewski, Andrew Z. ; Lofton-Day, Catherine. / Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. In: PLoS One. 2008 ; Vol. 3, No. 11.
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abstract = "Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths despite the fact that detection of this cancer in early stages results in over 90{\%} survival rate. Currently less than 45{\%} of at-risk individuals in the US are screened regularly, exposing a need for better screening tests. We performed two case-control studies to validate a blood-based test that identifies methylated DNA in plasma from all stages of CRC. Methodology/Principal Findings: Using a PCR assay for analysis of Septin 9 (SEPT9) hypermethylation in DNA extracted from plasma, clinical performance was optimized on 354 samples (252 CRC, 102 controls) and validated in a blinded, independent study of 309 samples (126 CRC, 183 controls). 168 polyps and 411 additional disease controls were also evaluated. Based on the training study SEPT9-based classification detected 120/252 CRCs (48{\%}) and 7/102 controls (7{\%}). In the test study 73/126 CRCs (58{\%}) and 18/183 control samples (10{\%}) were positive for SEPT9 validating the training set results. Inclusion of an additional measurement replicate increased the sensitivity of the assay in the testing set to 72{\%} (90/125 CRCs detected) while maintaining 90{\%} specificity (19/183 for controls). Positive rates for plasmas from the other cancers (11/96) and non-cancerous conditions (41/315) were low. The rate of polyp detection (>1 cm) was ∼20{\%}. Conclusions/Significance: Analysis of SEPT9 DNA methylation in plasma represents a straightforward, minimally invasive method to detect all stages of CRC with potential to satisfy unmet needs for increased compliance in the screening population. Further clinical testing is warranted.",
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