nature publishing group ORIGINAL CONTRIBUTIONS COLON/SMALL BOWEL 1 © 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY INTRODUCTION Colorectal cancer is the third most common cancer and accounts for ~10 percent of cancer-related deaths overall (1). In addition, one in three people who develop colorectal cancer will ultimately die because of this disease. Detection and removal of early-stage colorectal cancers have been shown to reduce the risk of this tumor (2,3). Over the last decade, colonoscopy has become the preferred screening test to detect colorectal cancer and is endorsed by sev- eral national guidelines because it is capable of detecting polyps and cancers with high accuracy (4–6). Apart from this, it is also therapeutic by virtue of its ability to remove polyps and early can- cers. Despite its high sensitivity and safety, acceptance of screen- ing colonoscopy remains rather low within the general public, with the need for cathartic bowel preparation being one of the main reasons (7,8). herefore, sensitive stool- or blood-based tests could be attractive for people who object screening colonoscopy. Stool-based tests such as guaiac-based fecal occult blood tests can reduce colorectal cancer mortality when applied annually or bien- nially but have limited sensitivity for colorectal cancers and par- ticularly adenomas (9). Furthermore, guaiac-based fecal occult blood test reacts with non-human blood in food, and dietary restrictions are required before sample collection. Immunochem- ical fecal occult blood tests to speciically detect human occult blood in feces have been developed to overcome the limitations of guaiac-based fecal occult blood tests, but they have not shown better overall test performance compared with guaiac-based fecal occult blood test (4). Stool tests based on the detection of DNA mutations in stool have been proposed and tested in prospective trials (10). However, because of unsatisfying performance, these tests cannot be recommended currently. Epigenetic DNA modiication, such as aberrant hypermethyla- tion, is a common feature of human cancers and is already found in Methylation of NEUROG1 in Serum Is a Sensitive Marker for the Detection of Early Colorectal Cancer Andreas Herbst, PhD 1 , Konstanze Rahmig 1 , Petra Stieber, MD 2 , Alexander Philipp 1 , Andreas Jung, PhD 3 , Andrea Ofner 1 , Alexander Crispin, MD 4 , Jens Neumann, MD 3 , Rolf Lamerz, MD 1 and Frank T. Kolligs, MD 1 OBJECTIVES: Colorectal cancer is the third most common cancer and a major cause of cancer-related deaths. Early detection of colonic lesions can reduce the incidence and mortality of colorectal cancer. Colonoscopy is the screening test for colorectal cancer with the highest efficacy, but its acceptance in the general public is rather low. To identify suitable tumor-derived markers that could detect colorectal cancer in blood samples, we analyzed the methylation status of a panel of genes in sera of affected patients. METHODS: Using methylation-specific quantitative PCR, we analyzed the methylation of ten marker genes in sera of healthy individuals and patients with colorectal cancer. RESULTS: Only HLTF, HPP1/TPEF, and NEUROG1 DNA methylation was detectable in at least 50% of patients with colorectal cancers. Whereas HLTF and HPP1/TPEF preferentially detected advanced and me- tastasized colorectal cancers, NEUROG1 methylation was detectable in UICC stages I–IV at a similar rate. Compared with other methylation markers, such as ALX4, SEPT9, and vimentin, NEUROG1 shows a higher sensitivity for colorectal cancer at UICC stages I and II. At a specificity of 91%, NEUROG1 reached a sensitivity of 61% (confidence interval, 50.4–70.6%) for the detection of colorectal cancers. Furthermore, detection of NEUROG1 methylation was independent of age and gender. CONCLUSIONS: Methylation of the NEUROG1 gene is frequently found in sera of patients with colorectal cancers independent of tumor stage. The quantitative detection of NEUROG1 DNA methylation in serum is a suitable approach for the non-invasive screening for asymptomatic colorectal cancer. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg Am J Gastroenterol advance online publication, 15 February 2011; doi:10.1038/ajg.2011.6 1 Department of Medicine II, University of Munich, Munich, Germany; 2 Institute of Clinical Chemistry , Munich, Germany; 3 Institute of Pathology, University of Munich, Munich, Germany; 4 Institute of Medical Informatics, Biometry and Epidemiology, Munich, Germany. Correspondence: Frank T. Kolligs, MD, Department of Medicine II, University of Munich, Marchioninistrasse 15, Munich 81377, Germany . E-mail: fkolligs@med.uni-muenchen.de Received 23 July 2010; accepted 21 December 2010