Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease

• Published in: Alimentary pharmacology & therapeutics Vol. 37; no. 5; pp. 546 - 554
• Main Authors: Kisiel, J. B., Yab, T. C., Nazer Hussain, F. T., Taylor, W. R., Garrity‐Park, M. M., Sandborn, W. J., Loftus, E. V., Wolff, B. G., Smyrk, T. C., Itzkowitz, S. H., Rubin, D. T., Zou, H., Mahoney, D. W., Ahlquist, D. A.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01-03-2013
• Subjects: Adult; Aged; Biological and medical sciences; Biomarkers, Tumor - genetics; Bone morphogenetic protein 3; Cancer; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - genetics; Crohn's disease; Digestive system; DNA; DNA methylation; DNA sequencing; DNA, Neoplasm - analysis; Dysplasia; Feces; Feces - chemistry; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genetic Markers - genetics; Humans; Inflammatory bowel diseases; Inflammatory Bowel Diseases - diagnosis; Inflammatory Bowel Diseases - genetics; Male; Medical sciences; Middle Aged; Mutation; Neoplasia; Other diseases. Semiology; Pharmacology. Drug treatments; Predictive Value of Tests; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Ulcerative colitis; Vimentin; Human; Rectal disease; Colorectal cancer; Malignant tumor; Inflammatory disease; Colonic disease; Inflammatory bowel disease; Crohn disease; Digestive diseases; Intestinal disease; Diagnosis; Feces; Genetic testing; Detection; Cancer; Ulcerative colitis
• ISSN: 0269-2813; 1365-2036
• DOI: 10.1111/apt.12218

Summary
Background
Current approaches to the detection of colorectal neoplasia associated with inflammatory bowel disease (IBD‐CRN) are suboptimal.
Aim
To test the feasibility of using stool assay of exfoliated DNA markers to detect IBD‐CRN.
Methods
This investigation comprised tissue and stool studies. In the tissue study, gene sequencing and methylation assays were performed on candidate genes using tissue DNA from 25 IBD‐CRNs and from 25 IBD mucosae without CRN. Mutations on p53, APC, KRAS, BRAF or PIK3CA genes were insufficiently informative, but several aberrantly methylated genes were highly discriminant. In the stool study, we evaluated candidate methylated genes (vimentin, EYA4, BMP3, NDRG4) in a prospective blinded study on buffered stools from 19 cases with known IBD‐CRN and 35 age‐ and sex‐matched IBD controls without CRN. From stool‐extracted DNA, target genes were assayed using quantitative allele‐specific real‐time target and signal amplification method.
Results
IBD‐CRN cases included 17 with ulcerative colitis (UC) and two with Crohn's disease (CD); nine had cancer and 10 had dysplasia. Controls included 25 with UC and 10 with CD. Individually, BMP3, vimentin, EYA4 and NDRG4 markers showed high discrimination in stools with respective areas under the ROC curve of 0.91, 0.91, 0.85 and 0.84 for total IBD‐CRN and of 0.97, 0.97, 0.95 and 0.85 for cancer. At 89% specificity, the combination of BMP3 and mNDRG4 detected 9/9 (100%) of CRC and 80% of dysplasia, 4/4 (100%) of high grade and 4/6 (67%) of low grade.
Conclusion
These findings demonstrate the feasibility of stool DNA testing for non‐invasive detection of colorectal neoplasia associated with inflammatory bowel disease.