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

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

doi:10.1186/s13148-019-0757-3

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

102 Citations (Scopus)

Abstract

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- A nd 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 language	English
Article number	158
Journal	Clinical Epigenetics
Volume	11
Issue	1
Number of pages	14
ISSN	1868-7075
DOIs	https://doi.org/10.1186/s13148-019-0757-3
Publication status	Published - 2019

Keywords

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

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10.1186/s13148-019-0757-3

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Jensen, S. Ø., Øgaard, N., Ørntoft, M. B. W., Rasmussen, M. H., Bramsen, J. B., Kristensen, H., Mouritzen, P., Madsen, M. R., Madsen, A. H., Sunesen, K. G., Iversen, L. H., Laurberg, S., Christensen, I. J., Nielsen, H. J., & Andersen, C. L. (2019). Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer- A clinical biomarker discovery and validation study. Clinical Epigenetics, 11(1), Article 158. https://doi.org/10.1186/s13148-019-0757-3

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title = "Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer- A clinical biomarker discovery and validation study",

abstract = "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- A nd 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.",

keywords = "Cancer, Circulating tumour DNA, Colorectal cancer, DNA methylation, Early detection, Epigenetic biomarkers, Liquid biopsy",

author = "Jensen, {Sarah {\O}strup} and Nadia {\O}gaard and {\O}rntoft, {Mai Britt Worm} and Rasmussen, {Mads Heilskov} and Bramsen, {Jesper Bertram} and Helle Kristensen and Peter Mouritzen and Madsen, {Mogens R{\o}rb{\ae}k} and Madsen, {Anders Husted} and Sunesen, {K{\aa}re Gotschalck} and Iversen, {Lene Hjerrild} and S{\o}ren Laurberg and Christensen, {Ib Jarle} and Nielsen, {Hans J{\o}rgen} and Andersen, {Claus Lindbjerg}",

year = "2019",

doi = "10.1186/s13148-019-0757-3",

language = "English",

volume = "11",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "BioMed Central",

number = "1",

}

Jensen, SØ , Øgaard, N , Ørntoft, MBW , Rasmussen, MH , Bramsen, JB, Kristensen, H, Mouritzen, P, Madsen, MR, Madsen, AH, Sunesen, KG, Iversen, LH , Laurberg, S, Christensen, IJ, Nielsen, HJ & Andersen, CL 2019, 'Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer- A clinical biomarker discovery and validation study', Clinical Epigenetics, vol. 11, no. 1, 158. https://doi.org/10.1186/s13148-019-0757-3

Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer- A clinical biomarker discovery and validation study. / Jensen, Sarah Østrup ; Øgaard, Nadia ; Ørntoft, Mai Britt Worm et al.
In: Clinical Epigenetics, Vol. 11, No. 1, 158, 2019.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer- A clinical biomarker discovery and validation study

AU - Jensen, Sarah Østrup

AU - Øgaard, Nadia

AU - Ørntoft, Mai Britt Worm

AU - Rasmussen, Mads Heilskov

AU - Bramsen, Jesper Bertram

AU - Kristensen, Helle

AU - Mouritzen, Peter

AU - Madsen, Mogens Rørbæk

AU - Madsen, Anders Husted

AU - Sunesen, Kåre Gotschalck

AU - Iversen, Lene Hjerrild

AU - Laurberg, Søren

AU - Christensen, Ib Jarle

AU - Nielsen, Hans Jørgen

AU - Andersen, Claus Lindbjerg

PY - 2019

Y1 - 2019

N2 - 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- A nd 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.

AB - 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- A nd 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.

KW - Cancer

KW - Circulating tumour DNA

KW - Colorectal cancer

KW - DNA methylation

KW - Early detection

KW - Epigenetic biomarkers

KW - Liquid biopsy

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U2 - 10.1186/s13148-019-0757-3

DO - 10.1186/s13148-019-0757-3

M3 - Journal article

C2 - 31727158

AN - SCOPUS:85075113935

SN - 1868-7075

VL - 11

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

M1 - 158

ER -

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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