Genetic mutation load predicts progression of Barrett's esophagus

Reuters Health Information: Genetic mutation load predicts progression of Barrett's esophagus

Genetic mutation load predicts progression of Barrett's esophagus

Last Updated: 2015-06-10

By Will Boggs MD

NEW YORK (Reuters Health) - An increased load of genetic mutations predicts progression of Barrett's esophagus to adenocarcinoma, according to results of a case-control study.

Up to six in 1,000 patients with Barrett's esophagus (BE) may progress to esophageal adenocarcinoma each year, but currently dysplasia detected on endoscopic surveillance is the only clinical biomarker to stratify the risk of progression, researchers note in The American Journal of Gastroenterology, online May 26.

To gain more information, Dr. Nicholas J. Shaheen from the University of North Carolina, Chapel Hill, and colleagues studied 23 patients whose BE progressed (cases) and 46 patients whose BE did not progress (controls).

The mutational load (ML), ranging from 0 to 10, quantified the degree of cumulative genetic derangement present at 10 previously implicated genomic loci.

The mean ML at index biopsy was more than five times higher in cases than in controls (2.21 vs. 0.42; p<0.0001), the researchers found.

None of the cases had an ML of 0 on their pre-progression biopsy, compared to 54% of controls.

An ML of 1 or more yielded the highest accuracy for predicting progression (89.9%), though the test was most sensitive at a threshold ML of 0.5.

The most frequent loci mutated in cases included 9p, 17p, and 5q, but the most discriminating results were achieved when all 10 loci were used in the analysis.

"Better risk stratification will have implications in the frequency of surveillance endoscopy, as well as treatment decisions for ablative therapy in high-risk individuals," the researchers conclude. "The results of this study provide support for the potential use of ML as a predictive biomarker in low-risk BE patients to assess for the risk of progression to malignancy."

Other experts cautioned that ML is not yet ready for prime time, though the concept is promising.

"It will require extensive validations," Dr. William M. Grady from Fred Hutchinson Cancer Research Center in Seattle, Washington, told Reuters Health by email. "Most hospital labs cannot do this analysis."

Dr. Sebastian Zeki from Hutchison/MRC Research Centre's Cancer Unit in Cambridge, UK, agreed.

"Most pathology labs are not currently set up to do this kind of analysis but with the emergence of next-generation sequencing you might envisage a time in the near future where this kind of molecular stratification could be done routinely for Barrett's," Dr. Zeki said. "I don't think this future is too far away."

"The take home message is that the molecular changes may predate any concerning histological changes by a number of years," Dr. Zeki concluded in an email to Reuters Health. "This is both encouraging for molecular and sequencing technologies, demonstrating that they can be more sensitive than the histopathologist's eye, and also concerning that we should not necessarily be 100% reassured even with a normal H&E (hematoxylin and eosin stain)."

Interpace Diagnostics supported the trial, employed three of the 11 authors, and provided research funding to Dr. Shaheen.

Dr. Shaheen did not respond to a request for comments.


Am J Gastroenterol 2015.

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