NEW YORK (GenomeWeb News) – An international consortium of researchers co-led by teams at the Fred Hutchinson Cancer Research Center in Seattle and the QIMR Berghofer Medical Research Institute in Queensland, Australia has identified four genetic variants associated with an increased risk of esophageal cancer and a precursor condition called Barrett's esophagus.
The researchers conducted a genome-wide study that included nearly 5,600 cases of esophageal carcinoma and precancerous Barrett's esophagus and more than 10,000 controls. They 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.
"We report the first genome-wide association study of esophageal adenocarcinoma and the first to examine this cancer together with its precancerous lesion, Barrett's esophagus," the researchers wrote in a study published in the current issue of Nature Genetics. "[T]hese findings suggest that much of the genetic basis for esophageal adenocarcinoma lies in the development of Barrett's esophagus, rather than in the progression from Barrett's esophagus to esophageal adenocarcinoma."
The researchers used data collected by the international Barrett's and Esophageal Adenocarcinoma Consortium, or BEACON, an open scientific forum for research into the causes and prevention of esophageal cancer and Barrett's esophagus involving more than 40 scientists in North America, Europe, and Australia. The data and DNA specimens came from 15 international studies conducted during the past 20 years, they noted.
In the first phase of the two-part study, the researchers analyzed 1,516 esophageal adenocarcinoma cases, 2,416 Barrett's esophagus cases, and 3,209 controls — all of European ancestry — and added in another 1,022 cancer-free controls from a melanoma study to increase statistical power. All samples were genotyped using the Illumina HumanOmni1-Quad platform.
The investigators selected 94 associated SNPs for replication, and of these 87 were genotyped in 874 histologically confirmed esophageal adenocarcinoma cases from the Stomach and Oesophageal Cancer Study, 759 confirmed Barrett's Esophagus cases from the UK Barrett's Esophagus Gene Study, and 6,911 controls. The samples all came from people who self-identified as Caucasian and were genotyped on a Fluidigm 96.96 Dynamic Array.
In the combined case group, three loci reached genome-wide significance: rs10419226 at 19p13 in CRTC1, rs11789015 at 9q22 in BARX1, and rs2687201 at 3p14 near transcription factor FOXP1 — a gene encoding a transcription factor that regulates esophageal development.
In addition, the researchers noted that a previous study conducted by BEACON had found an association with Barrett's esophagus at 16q24 involving rs9936833. "Here we found clear evidence that this locus is also associated with esophageal carcinoma," they wrote in the paper published online yesterday.
"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," corresponding author Thomas Vaughan, a member of the Epidemiology Program in the Public Health Sciences Division at Fred Hutchinson Cancer Research Center, said in a statement. "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."
Barrett's esophagus is associated with chronic heartburn and affects an estimated 1 million to 2 million Americans. Though the risk of developing esophageal cancer in a person with Barrett's esophagus is a fraction of 1 percent per year, the majority of patients with invasive esophageal cancer die within a year of diagnosis.