Researchers Identify Four Genetic Variants Linked to Esophageal Cancer and Barrett’s Esophagus
An international consortium co-led by researchers at Fred Hutchinson Cancer Research Center and the QIMR Berghofer Medical Research Institute in Australia has identified four genetic variants associated with an increased risk of esophageal cancer and its precursor, Barrett’s esophagus.
The findings, by corresponding author Thomas L. Vaughan, MD, MPH, of the Epidemiology Program in the Public Health Sciences Division at Fred Hutchinson, were published online ahead of print in Nature Genetics. Dr Vaughan co-led the project with coauthor David Whiteman, PhD, Head of the Cancer Control Group at QIMR.
“Epidemiologic findings, largely based on the work of BEACON [Barrett’s and Esophageal Adenocarcinoma Consortium] investigators, clearly demonstrate that environmental factors such as obesity, gastroesophageal reflux, smoking, and diet are largely responsible for the rapidly increasing incidence and mortality from esophageal adenocarconima,” said Dr. Vaughan, who serves as BEACON’s Chair and is also a Professor of Epidemiology at the University of Washington School of Public Health. “However, a growing body of evidence also suggests an important role for inherited susceptibility.”
Study Details
To better understand the role of genetics in Barrett’s and esophageal cancer, Dr. Vaughan and his BEACON colleagues pooled data and DNA specimens from 15 international studies conducted in the past 20 years to estimate the heritability of these conditions and identify genetic variants associated with increased risk. Altogether they gathered DNA samples and lifestyle risk-exposure data from more than 8,000 study participants, including about 5,500 with esophageal cancer or Barrett’s esophagus and about 3,200 participants without these conditions who served as a comparison group.
The DNA samples were genotyped at Fred Hutchinson using a high-density array that allowed for the simultaneous and accurate assessment of more than 1 million genetic variants. To increase the statistical power of the study and its ability to identify potential causal genetic mutations, information on control subjects gleaned from public data repositories was added to the mix. The data analysis was conducted at the University of Washington in collaboration with the QIMR research group in Queensland.
Strong Role of Inherited Susceptibility in Early-Stage Disease
After combing through all of the data, the researchers identified genetic variants at three locations—on chromosomes 3, 9, and 19—as being significantly associated with esophageal adenocarcinoma and Barrett’s esophagus. In addition, they found that a genetic variant on chromosome 16 that had been previously linked to Barrett’s esophagus was also associated with an increased risk of esophageal adenocarcinoma.
Dr. Vaughan and colleagues also found that the role of inherited susceptibility to this cancer appears to be much stronger in the early stages of disease—that is, the development of Barrett’s esophagus—rather than the progression of Barrett’s to cancer.
“These findings establish strong starting points for further epidemiologic studies to pin down the causal variants, and laboratory studies to identify the mechanisms by which the causal variants might affect the development of Barrett’s esophagus and esophageal adenocarcinoma,” Dr. Vaughan said. “The fact that all four of the new loci are in or near genes associated with early development of the esophagus or already associated with oncogenic activity is particularly exciting, as it implies that we may be close to finding some important pathways in the development of this highly fatal disease.”
Ultimately, the researchers believe these findings will contribute to the development of new screening tools to identify those at highest risk of esophageal adenocarcinoma and its precursor, particularly when combined with established risk factors such as obesity and gastric reflux. “Down the line we anticipate that a better understanding of the pathophysiology of these diseases will lead to better and earlier treatments,” Dr. Vaughan said.
The National Cancer Institute provided primary funding for this research.
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