DNA Methylation and Mutation of Small Colonic Neoplasms in Ulcerative Colitis and Crohn's Colitis: Implications for Surveillance.
Stool DNA testing in patients with inflammatory bowel disease (IBD) may detect colorectal cancer and advanced precancers with high sensitivity; less is known about the presence of DNA markers in small IBD lesions, their association with metachronous neoplasia, or contribution to stool test positivity.



At a single center in 2 blinded phases, we assayed methylated bone morphogenic protein 3, methylated N-Myc downstream-regulated gene 4, and mutant KRAS in DNA extracted from paraffin-embedded benign lesions, and matched control tissues of patients with IBD, who were followed for subsequent colorectal dysplasia. Stool samples from independent cases and controls with lesions <1 cm or advanced neoplasms were assayed for the same markers.



Among IBD lesions (29 low-grade dysplasia, 19 serrated epithelial change, and 10 sessile serrated adenoma/polyps), the prevalence of methylation was significantly higher than in mucosae from 44 matched IBD controls (P < 0.0001 for methylated bone morphogenic protein 3 or methylated N-Myc downstream-regulated gene 4). KRAS mutations were more abundant in serrated epithelial change than all other groups (P < 0.001). Subsequent dysplasia was not associated with DNA marker levels. In stools, the sensitivity of methylated bone morphogenic protein 3 as a single marker was 60% for all lesions <1 cm, 63% for low-grade dysplasia ≥1 cm and 81% for high-grade dysplasia/colorectal cancer, all at 91% specificity (P < 0.0001).



Selected DNA markers known to be present in advanced IBD neoplasia can also be detected in both tissues and stools from IBD patients with small adenomas and serrated lesions. Mutant KRAS exfoliated from serrated epithelial change lesions might raise false-positive rates. These findings have relevance to potential future applications of stool DNA testing for IBD surveillance.
*Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; †Department of Internal Medicine, Rhode Island Memorial Hospital, Pawtucket, Rhode Island; ‡Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota; and §Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
David H
DH
Johnson
William R
WR
Taylor
Mohammed M
MM
Aboelsoud
Patrick H
PH
Foote
Tracy C
TC
Yab
Xiaoming
X
Cao
Thomas C
TC
Smyrk
Edward V
EV
Loftus
Douglas W
DW
Mahoney
David A
DA
Ahlquist
John B
JB
Kisiel
D000236:Adenoma / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D055398:Bone Morphogenetic Protein 3 / Q000235:genetics; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000150:complications*; D003110:Colonic Neoplasms / Q000150:complications / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D003424:Crohn Disease / Q000150:complications*; D004247:DNA / Q000032:analysis*; D019175:DNA Methylation; D004311:Double-Blind Method; D005243:Feces / Q000737:chemistry; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011159:Population Surveillance; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012680:Sensitivity and Specificity
C525757:BMP3 protein, human; D014408:Biomarkers, Tumor; D055398:Bone Morphogenetic Protein 3; C117307:KRAS protein, human; D004247:DNA; D016283:Proto-Oncogene Proteins p21(ras)