Journal
CLINICAL EPIGENETICS
Volume 11, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13148-019-0757-3
Keywords
DNA methylation; Epigenetic biomarkers; Cancer; Colorectal cancer; Liquid biopsy; Circulating tumour DNA; Early detection
Categories
Funding
- Danish Cancer Society [R107-A7035, R133-A8520-00-S41, R146-A9466-16-S2]
- Danish Council for Strategic Research [1309-00006B]
- Danish Council for Independent Research [4183-00619]
- Novo Nordisk Foundation [NNF14OC0012747, NNF17OC0025052]
- Neye Foundation
- Dansk Kraeftforskningsfond
- Harboefonden
- Augustinus Foundation
- Kornerup Fund
- Axel Muusfeldt Fund
- KID Fund
- Toyota Fund
- Aage and Johanne Louis-Hansen Fund
- A.P. Moeller and Chastine Mc-Kinney Moeller Foundation
- Aase and Ejnar Danielsen Fund
- Inger Bonnen Fund
- Hans and Nora Buchard Fund
- Sofus C.E. Friis Fund
- Eva and Henry Fraenkel Fund
- Sven and Ina Hansen Fund
- Henrik Henriksen Fund
- Humanitarian Fund
- IMK Fund
- Obel Family Fund
- Krista, and Viggo Petersen Fund
- Foundation Jochum
- The Jorgen Holm Fund
- Elna and Jorgen Fagerholdt Fund
- P.M. Christiansen Family Fund
- Walter and O. Kristiane Christensen Fund
- The Orient Fund
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available