Biomarker May Help Predict Esophageal Cancer : Survivin gene expression in biopsy specimens may identify Barrett's patients at higher risk for cancer.


TUCSON, ARIZ. — High levels of survivin gene expression may identify patients with Barrett's esophagus who are at risk for developing precancerous dysplasia, Daniel Vallböhmer, M.D., reported at the annual meeting of the Central Surgical Association.

The development of adenocarcinoma associated with Barrett's esophagus is thought to be a “multistep process” following a sequence of reflux, metaplasia, dysplasia, and then adenocarcinoma.

Researchers know that acid reflux damage to the esophagus and genetic factors initiate the replacement of squamous epithelium with cardiac mucosa, and then the intestinal metaplasia characteristic of Barrett's esophagus, said Dr. Vallböhmer of the division of thoracic and foregut surgery at the University of Southern California, Los Angeles.

Clinicians are often unable to classify patients by the steps in the sequence, he said, even after endoscopy or histology has been performed. “The major goal is to develop markers that can predict which patients with intestinal metaplasia or low-grade dysplasia will develop cancer” and which ones will not, although he noted that “we are far” from being able to do that.

Dr. Vallböhmer and his colleagues targeted their research on survivin, a member of the inhibitor-of-apoptosis family of proteins.

Avoidance of apoptosis is one of six major pathways described as necessary for the development of adenocarcinoma. The others are growth self-sufficiency, insensitivity to antigrowth signals, limitless replicative potential, sustained angiogenesis, and invasion (Lancet 2002;360:1587–9).

The investigators obtained endoscopic biopsies from 17 control patients with nonacid reflux and no esophagitis, 16 control patients with acid reflux and esophagitis, 12 patients with low- or high-grade dysplasia, and 45 patients with esophageal adenocarcinoma. They used a laser to microdissect tissue of interest from each biopsy specimen.

All patients stopped taking proton pump inhibitors 2 weeks before they underwent endoscopic biopsies.

The levels of survivin expressed in esophageal biopsies increased with the severity of histopathology in the biopsies.

The control groups and patients with Barrett's metaplasia had similar, low levels of survivin expression. But the expression of survivin significantly increased in a stepwise manner from patients with Barrett's intestinal metaplasia to patients with dysplasia and then to patients with adenocarcinoma.

“Survivin gene expression might be used in the future to distinguish Barrett's metaplasia from dysplasia,” Dr. Vallböhmer said.

The investigators were not able to find any clinicopathological factors that were significantly associated with the expression of survivin in adenocarcinomas, leading them to think that survivin expression “may not be a useful marker in determining the prognosis of esophageal adenocarcinoma,” he said.

But the findings lead us further into an understanding of the molecular biologic mechanisms related to the progression from an irritated, injured esophageal epithelium to precancerous lesions and frank esophageal cancer, Rodney Landreneau, M.D., told this newspaper. He agreed with the investigators that “these findings alone do not give us insight into relative cancer risk or prognosis for patients with histologic evidence of mucosal dysplasia and survivin expression.”

According to Dr. Landreneau, professor of cardiothoracic surgery at the University of Pittsburgh, the findings may be an event related to repeated acid reflux injury and a marker of ongoing repair or the patients' response to the injurious effects of chronic reflux.

“Certainly this interesting finding should be explored further to determine the prognostic significance and possible means of reversing these molecular changes if they are involved in the evolutionary pathway toward the development of esophageal cancer,” Dr. Landreneau said.

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