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Evolution of esophageal cancer

New study pinpoints two characteristics that predict whether precancerous Barrett's esophagus will progress to cancer
Drs. Carlo Maley, right, and Tom Paulson
Drs. Carlo Maley, right, and Tom Paulson and colleagues have found cell characteristics that may help predict esophageal-cancer progression. Photo by Todd McNaught

Survival-of-the-fittest strategies are credited with evolutionary events from the extinction of dinosaurs to the emergence of the two-legged stance of humans. Scientists believe that similar evolutionary tactics underlie the development of cancer, a condition in which some abnormal cells acquire characteristics that give them a survival advantage over their healthy neighbors.

A recent center study now reveals the combination of acquired characteristics that predicts whether cells associated with a precancerous condition called Barrett's esophagus will progress to full-blown esophageal cancer. The findings could eventually help scientists design treatments to prevent cancers from spreading.

In a study published in the Oct. 15 issue of Cancer Research, Dr. Carlo Maley and colleagues in Dr. Brian Reid's lab in the Human Biology and Public Health Sciences divisions found that progression to cancer was related to a combination of two factors: the size of the patch, or clone, of precancerous cells and whether those cells displayed an abnormality called genetic instability. Genetic instability is characterized by the accumulation of numerous chromosome defects that the cell is unable to fix. The condition is often brought on by defects in cell division and the erosion of the protective caps on the ends of chromosomes called telomeres.

Previous studies have focused on the role of either the size of the area of precancerous cells or genetic instability in cancer progression. Although each factor plays a role, the new study demonstrates that for esophageal cancer, a combination of both characteristics is a better predictor of cancer than either alone.

Unique opportunity

Maley said that the new study was made possible because Barrett's esophagus presents a unique opportunity for scientists to study cancer progression.

"Patient's with Barrett's undergo periodic surveillance with endoscopy, which makes it possible to measure the size of the affected area and to remove samples of esophageal tissue to examine which genetic abnormalities are present in cells from the affected area," he said. "This allowed us to simultaneously evaluate the effect of size and genetic instability."

Reid's lab leads a longstanding research project on Barrett's esophagus, a condition caused by excessive acid reflux that affects the tube that carries food from the mouth to the stomach. Other investigators who are key members of the effort include Dr. Tom Vaughan, who conducts studies to examine environmental and dietary exposures that affect esophageal-cancer progression, and Dr. Peter Rabinovitch, who has led the group's research on genetic instability. Co-authors of the new study included Dr. Patricia Galipeau, Dr. Xiaohong Li, Rissa Sanchez, Dr. Tom Paulson and Dr. Patricia Blount.

Each year, about 1 percent of Barrett's esophagus patients develop esophageal cancer. Thanks to regular endoscopic surveillance to detect cancer early — which involves inserting a flexible fiber-optic tube through the mouth into the esophagus to take biopsy samples — patients in Reid's Seattle Barrett's Esophagus Program are more than 80 percent likely to survive if cancer develops. That compares to a survival rate of only about 5 percent for patients who do not undergo such surveillance.

Statistical methods

In the current study, the researchers examined the size of the affected area as well as several genetic abnormalities in biopsies taken from 267 patients with Barrett's esophagus who were followed to determine whether cancer developed. Maley developed statistical methods that allowed him to determine the likelihood that cancer would develop from certain combinations of characteristics in the biopsy samples.

"Based on what we know about evolution, we'd reason that the larger the population of cells, the more likely the chance that one could pick up a mutation that will cause cancer," he said. Yet a 2000 study led by colleague Dr. Rebecca Rudolph had shown that Barrett's patients who had only a short segment of their esophagus affected with the condition were only slightly less to develop cancer than patient's with long-segment disease.

Maley speculated that the reason for this discrepancy might be that the researchers needed to focus on the size of a specific subpopulation of cells — that is, cells that had particular genetic defects, which Reid's group had shown were associated with cancer.

Using this approach, Maley and colleagues found that patches of cells containing either a mutation in a gene called p53 (a gene whose loss promotes genetic instability), or that were aneuploid (missing chromosomes) or tetraploid (having extra chromosomes) were associated with an increased risk of cancer that was dependent on the size of the tissue area containing these defects. For example a 6-centimeter patch of cells in which at least one copy of p53 was missing was more than three times as likely to progress to cancer as a 1-centimeter patch of those cells. Similarly, cancer was nearly four times more likely to develop from 6-centimeter patches that were aneuploid or tetraploid compared to a 1-centimeter patch.

Maley said that the results suggest that agents that limit the spread of certain subpopulations of precancerous cells — those that are aneuploid, tetraploid or have p53 defects — could potentially offer significant clinical benefits. "If we could delay cancer by 10 years, most patients with Barrett's would die of something else," he said.

Vaughan and Reid are conducting studies to evaluate whether nonsteroidal anti-inflammatory drugs (NSAIDs), which include common analgesics like aspirin, could have this effect.

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