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Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer-a clinical biomarker discovery and validation study

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  • Sarah Østrup Jensen
  • Nadia Øgaard
  • Mai-Britt Worm Ørntoft
  • Mads Heilskov Rasmussen
  • Jesper Bertram Bramsen
  • Helle Kristensen
  • Peter Mouritzen
  • Mogens Rørbæk Madsen
  • Anders Husted Madsen
  • Kåre Gotschalck Sunesen
  • Lene Hjerrild Iversen
  • Søren Laurberg
  • Ib Jarle Christensen
  • Hans Jørgen Nielsen
  • Claus Lindbjerg Andersen
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BACKGROUND: Early detection plays an essential role to reduce colorectal cancer (CRC) mortality. While current screening methods suffer from poor compliance, liquid biopsy-based strategies for cancer detection is rapidly gaining promise. Here, we describe the development of TriMeth, a minimal-invasive blood-based test for detection of early-stage colorectal cancer. The test is based on assessment of three tumour-specific DNA methylation markers in circulating cell-free DNA.

RESULTS: A thorough multi-step biomarker discovery study based on DNA methylation profiles of more than 5000 tumours and blood cell populations identified CRC-specific DNA methylation markers. The DNA methylation patterns of biomarker candidates were validated by bisulfite sequencing and methylation-specific droplet digital PCR in CRC tumour tissue and peripheral blood leucocytes. The three best performing markers were first applied to plasma from 113 primarily early-stage CRC patients and 87 age- and gender-matched colonoscopy-verified controls. Based on this, the test scoring algorithm was locked, and then TriMeth was validated in an independent cohort comprising 143 CRC patients and 91 controls. Three DNA methylation markers, C9orf50, KCNQ5, and CLIP4, were identified, each capable of discriminating plasma from colorectal cancer patients and healthy individuals (areas under the curve 0.86, 0.91, and 0.88). When combined in the TriMeth test, an average sensitivity of 85% (218/256) was observed (stage I: 80% (33/41), stage II: 85% (121/143), stage III: 89% (49/55), and stage IV: 88% (15/17)) at 99% (176/178) specificity in two independent plasma cohorts.

CONCLUSION: TriMeth enables detection of early-stage colorectal cancer with high sensitivity and specificity. The reported results underline the potential utility of DNA methylation-based detection of circulating tumour DNA in the clinical management of colorectal cancer.

Original languageEnglish
Article number158
JournalClinical Epigenetics
Volume11
Issue number1
Pages (from-to)158
ISSN1868-7075
DOIs
Publication statusPublished - 14 Nov 2019

    Research areas

  • Cancer, Circulating tumour DNA, Colorectal cancer, DNA methylation, Early detection, Epigenetic biomarkers, Liquid biopsy

ID: 58383638