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

Autor: Jensen SØ; Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark., Øgaard N; Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark., Ørntoft MW; Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark., Rasmussen MH; Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark., Bramsen JB; Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark., Kristensen H; Exiqon, Vedbæk, Denmark., Mouritzen P; Exiqon, Vedbæk, Denmark., Madsen MR; Herning Regional Hospital, Herning, Denmark., Madsen AH; Herning Regional Hospital, Herning, Denmark., Sunesen KG; Randers Regional Hospital, Randers, Denmark., Iversen LH; Department of Surgery, Aarhus University Hospital, Aarhus, Denmark., Laurberg S; Department of Surgery, Aarhus University Hospital, Aarhus, Denmark., Christensen IJ; Center for Surgical Research, Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark., Nielsen HJ; Center for Surgical Research, Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark.; Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Andersen CL; Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark. cla@clin.au.dk.
Jazyk: angličtina
Zdroj: Clinical epigenetics [Clin Epigenetics] 2019 Nov 14; Vol. 11 (1), pp. 158. Date of Electronic Publication: 2019 Nov 14.
DOI: 10.1186/s13148-019-0757-3
Abstrakt: 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.
Databáze: MEDLINE
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