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Clin Gastroenterol Hepatol. 2019 Apr;17(5):914-921.e5. doi: 10.1016/j.cgh.2018.05.004. Epub 2018 May 15.

Analysis of DNA Methylation at Specific Loci in Stool Samples Detects Colorectal Cancer and High-Grade Dysplasia in Patients With Inflammatory Bowel Disease.

Author information

1
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: kisiel.john@mayo.edu.
2
Department of Internal Medicine, Lovisenberg Hospital, Oslo, Norway; Clinical Medicine, University Hospital, University of Oslo, Oslo, Norway.
3
Department of Gastroenterology, Akershus University Hospital, University of Oslo, Oslo, Norway.
4
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
5
Exact Sciences Corporation, Madison, Wisconsin.
6
Department of Gastroenterology, Oslo University Hospital, Oslo, Norway.
7
Department of Gastroenterology, Akershus University Hospital, University of Oslo, Oslo, Norway; Clinical Medicine, University Hospital, University of Oslo, Oslo, Norway.
8
Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
9
Department of Internal Medicine, Lovisenberg Hospital, Oslo, Norway.

Abstract

BACKGROUND & AIMS:

Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are at increased risk for colorectal cancer (CRC). Analyses of DNA methylation patterns in stool samples have been reported to detect CRC in patients with IBD. We sought to validate these findings in larger cohorts and assess the accuracy of analysis of DNA methylation patterns in stool for detection of CRC and high-grade dysplasia (HGD) normalized to methylation level at ZDHHC1.

METHODS:

We obtained buffered, frozen stool samples from a US case-control study and from 2 European surveillance cohorts (referral or population based) of patients with chronic ulcerative colitis (n = 248), Crohn's disease (n = 82), indeterminate colitis (n = 2), or IBD with primary sclerosing cholangitis (n = 38). Stool samples were collected before bowel preparation for colonoscopy or at least 1 week after colonoscopy. Among the study samples, stools from individuals with IBD but without neoplasia were used as controls (n = 291). DNA was isolated from stool, exposed to bisulfite, and then assayed by multiplex quantitative allele-specific real-time target and signal amplification. We analyzed methylation levels of BMP3, NDRG4, VAV3, and SFMBT2 relative to the methylation level of ZDHHC1, and compared these between patients with CRC or HGD and controls.

RESULTS:

Levels of methylation at BMP3 and VAV3, relative to ZDHHC1 methylation, identified patients with CRC and HGD with an area under the curve value of 0.91 (95% CI, 0.77-1.00). Methylation levels at specific promotor regions of these genes identified 11 of the 12 patients with CRC and HGD, with 92% sensitivity (95% CI, 60%-100%) and 90% specificity (95% CI, 86%-93%). The proportion of false-positive results did not differ significantly among the case-control, referral cohort, and population cohort studies (P = .60) when the 90% specificity cut-off from the whole sample set was applied.

CONCLUSIONS:

In an analysis of stool samples from 3 independent studies of 332 patients with IBD, we associated levels of methylation at 2 genes (BMP3 and VAV3), relative to level of methylation at ZDHHC1, with detection of CRC and HGD. These methylation patterns identified patients with CRC and HGD with more than 90% specificity, and might be used in CRC surveillance.

KEYWORDS:

Biomarker; Complications; Neoplasm; Noninvasive Test; Prevention

PMID:
29775793
PMCID:
PMC6368476
[Available on 2020-04-01]
DOI:
10.1016/j.cgh.2018.05.004

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