Stool DNA highly accurate for IBD-associated colorectal neoplasms

People with long-standing inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC) and dysplasia. The degree of risk is known to increase with the extent and duration of disease, family history and the presence of primary sclerosing cholangitis.

To help detect early neoplasia, IBD patients are advised to undergo surveillance colonoscopies with random biopsies every one to two years — an approach that is problematic for many reasons. One is the unreliability of random biopsies, which sample only a small fraction of the colon mucosal surface. Even targeted biopsies using enhanced imaging techniques such as chromoendoscopy can miss lesions obscured by background inflammation.

In addition, there is little data on the ideal frequency for performing surveillance exams and little evidence to demonstrate their effectiveness. Gastroenterologist John B. Kisiel, M.D., points to a 2006 Cochrane meta-analysis by Collins, et al. that found no reduction in CRC deaths with surveillance colonoscopy. "The practice is endorsed because it may find cancers at an earlier stage, but it is invasive, and most patients don't comply very well, even those with access to good health care. The rate is half what it should be," he says.

Searching for an alternative, Dr. Kisiel wondered whether stool assay of exfoliated molecular markers, already a proven option for CRC screening in the general population, might be equally effective in IBD patients. He explains, "We know that the molecular changes in sporadic and IBD-CRC overlap. We wanted to know if we could find a panel of markers that would discriminate most cases of IBD-CRC from IBD without cancer at the tissue level. The aim was to assess for mutations in the genes p53, APC, BRAF and K-ras and abnormal methylation in the genes VIM, BMP3, EYA4 and septin 9."

Study process and findings

Dr. Kisiel and colleagues began by examining archived tissue from IBD patients with and without neoplasia, and then used the results to guide a study of stool samples from 19 patients with IBD-associated CRC and 35 matched controls. The findings were published in the March 2013 issue of Alimentary Pharmacology and Therapeutics.

As expected, the most informative mutation marker in the tissue study was p53, with mutations in 11 of 25 tumor samples. Three mutations were found on APC and four on K-ras. None were identified on BRAF and PIK3CA. Although specificity was 100 percent, sensitivity for all mutation markers was just 60 percent — similar to rates of DNA mutations in the same genes in sporadic CRC tissues.

Methylated DNA markers — which can indicate alterations in gene expression — fared better. All were discriminate for cancer. The top three — BMP3, VIM and EYA4 were included in the stool study based on receiver operating characteristic (ROC) areas > 0.80. Methylated NDGR4 (mNDGR4) was also included because of its high discrimination for sporadic CRC.

The same methodology was used in the stool segment of the study, and this time, the results were better than expected. Alone, methylated BMP3 (mBMP3) detected 100 percent of colorectal cancers and 84 percent of all neoplasms at 91 percent specificity. Combined mBMP3 and mNDRG4 detected 100 percent of colorectal cancers, 100 percent of high-grade dysplasia and 67 percent of low-grade dysplasia with 89 percent specificity. Stool markers were not affected by location nor were they significantly different in patients with ulcerative colitis compared to those with Crohn's disease.

Future feasibility

Although acknowledging that more studies are needed, Dr. Kisiel says these results clearly indicate promise for stool DNA testing as an accurate, noninvasive method for detecting colorectal cancers and precancers in IBD patients.

He explains that the test, which can be done at home and requires no colon preparation, might lead to better compliance as well as help distinguish patients needing more-frequent colonoscopies from those needing them less often.

A further step, he says, would be "to develop stool DNA testing to identify cancers above the colon — in the bile duct or small bowel, for instance — for which IBD patients might also be at risk."

For more information

Collins, PD et al. Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease. Cochrane Database of Systematic Reviews.

Kisiel JB, et al. Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. In press. Accessed May 5, 2013.