A disorder known as Barrett's esophagus (BE) affects some 200,000 Americans each year. The condition, which is caused by stomach acid damaging the lining of the esophagus, can lead to the development of a serious, potentially fatal cancer of epithelial tissue, known as esophageal adenocarcinoma (EAC).
In a new study, Carlo Maley, a researcher at Arizona State University's Biodesign Institute, uses evolutionary theory to make predictions about which BE patients will go on to develop cancer.
The results, which appear in the current issue of the journal Nature Communications, point the way toward more accurate medical assessments for patients with BE and the development of early-warning beacons of disease known as biomarkers.
The research highlights the power of studying genetic diversity as a reliable predictor of cancer development and spread in BE cases and potentially, across cancer types. Such evolutionary indices offer the prospect of more accurate, pre-symptomatic diagnosis of cancer, compared with traditional biomarkers based on specific genetic abnormalities.
"Less than 5 percent of people with Barrett's will develop esophageal cancer in their lifetimes, yet we spend a great deal of resources and emotional stress over monitoring everyone with that disease," Maley says. "We need better ways predict who is at risk and who can be reassured. Evolutionary theory provides novel ways to measure the underlying evolutionary process that drives the disease and thereby predict who is at risk."
Processes of evolution have given rise to the cornucopia of life on earth, through the twin paradigms of chance mutation and natural selection, promoting advantageous traits while weeding out those that are disadvantageous to the organism.
Unfortunately, cells that have become cancerous, furthering their own survival at the expense of their host, are also embedded in the evolutionary framework, using evolutionary strategies to further their lethal agenda.
As the author's note, BE provides an ideal laboratory for studying evolution in action. Cells in the esophagus bearing mutations can propagate to form clones, (collections of genetically identical cells). Selection acts to preserve those clones that convey a survival advantage to a developing tumor, allowing such clones to expand with time.
Despite the central importance of clonal expansion in the trajectory of cancerous tumors, the dynamics of clonal evolution, degree of clonal diversity and rates of clonal expansion had not been quantified prior to the new study.
The paper highlights an intriguing finding: in the case of BE, genetic diversity remains fixed from an early stage, rather than increasing over time. Only Barrett's lesions whose genetic diversity is above a given threshold develop into EAC, while the majority of cases do not. Rather than a step-wise expansion of clones with time, the data show a co-existence of multiple clones, which come and go at equal rates, maintaining a dynamic equilibrium of genetic diversity.
A more thorough understanding of the evolutionary dynamics of Barrett's clones is essential for understanding the factors driving cancer progression as well as for improved clinical management of the disease.
Currently, only a small percentage of Barrett's patients go on to develop esophageal cancer during their lifetime, but assessing the risk in particular individuals is challenging, costly, time consuming and error-prone.
Ongoing, endoscopic surveillance of BE patients aims to detect cancers in their early stages, where they may be addressed through minimally invasive means, but improved methods of risk assessment in BE populations could potentially save lives at reduced cost, zeroing in on those patients most likely to develop life-threatening disease.
Signs of illness
When food or liquid is swallowed, it passes through the esophagus — a hollow, muscular tube running from the throat to the stomach. Stomach acid and bile used to digest food, is normally prevented from rising up into the esophagus by the esophageal sphincter — a ring of muscle joining the stomach and lower esophagus. Stomach reflux, however, can force liquid from the stomach into the esophagus, potentially injuring the structure.
Patients with chronic acid reflux are at risk of developing Barrett's esophagus, whose symptoms include heartburn; a sour, burning sensation in the back of the throat; upper chest pain, chronic cough, laryngitis, and nausea.
In Barrett's esophagus, the normal tissue lining the esophagus is transformed into tissue resembling the lining of the intestine. Roughly 10 percent of people with chronic symptoms of gastro-esophageal reflux will develop Barrett's esophagus.
While Barrett's esophagus increases the risk of esophageal cancer, the disease remains rare, affecting less than 1 percent of BE patients per year. Nevertheless, those with BE are encouraged to undergo routine examinations of the esophagus to search for pre-cancerous or cancerous lesions and target them for early treatment.
Often, there are no specific symptoms associated with Barrett's esophagus. Diagnosis is carried out through endoscopy and biopsy. The American Gastroenterological Association recommends regular screening for those carrying multiple risk factors for BE, including white males over 50 years of age with a history of hiatal hernia, chronic gastro-esophageal reflux, smoking and/or obesity.
Progression to cancer
The current study examines cell samples brushed from the esophageal lining of 320 patients with BE. All patients underwent acid suppressive therapy and were cancer-free at the outset. Patients were evaluated for 11-130 months, during which 20 patients (or 6.3 percent) progressed to a cancerous stage.
Intriguingly, the new study also determined that the degree of genetic diversity in BE lesions does not tend to change over time. The finding suggests that evolutionary selection acting on BE clones is weak and that risk of cancer development is predetermined by a baseline level of diversity which remains invariant over time: highly diverse Barrett's lesions typically progress to cancerous stages while low diversity lesions do not.
Analysis of BE patients over time confirmed genetic diversity was indeed closely correlated with the likelihood of progression to esophageal cancer, further validating the results of earlier research from Maley's team. Diversity-based categorization of cases in the study identified all but one BE case progressing to cancer in 80-100 percent of simulations conducted. Surprisingly, clone size did not correlate with likelihood of disease progression.
The researchers also provide the first estimates of the rate of expansion and contraction of mutant clones occurring in a living subject. Results demonstrated that a dynamic equilibrium is at work in lesions, with clonal expansions and contractions roughly balancing each other out over time, leading to stable genetic diversity. (The point at which dynamic equilibrium is established for BE lesions has yet to be precisely determined.)
Clonal expansions without accompanying contractions were found to be rare, occurring on average once every 36.8 patient years, while clonal contractions occurred once every 22.1 patient years. In cases of clonal expansion, clones grew an average of 1.58 cm2 per year across the surface of the esophagus.
The data sheds new light on the evolutionary dynamics involved in the progression from BE to cancer, with important implications for clinical surveillance and early treatment. The findings further support measures of genetic diversity as universal biomarkers for assessing the risk of disease progression across multiple forms of cancer.