Patients with gastroesophageal reflux disease who also have a specific epidermal growth factor gene polymorphism appear to have a significantly increased risk for esophageal adenocarcinoma, a case-control study suggests.
Findings from this study of 309 patients being treated for esophageal cancer and 275 healthy matched controls could have implications for identifying patients at risk for developing esophageal adenocarcinoma (EAC), presented at the annual Gastrointestinal Cancers Symposium.
“We’ve known for some time that [gastroesophageal reflux disease] is a risk factor for esophageal cancer, but findings are the first to identify specific genetic markers that are linked with increased cancer risk in patients with GERD.”
Commented, “This is potentially important study that examines the role of EGF gene polymorphisms/SNPs [single nucleotide polymorphisms] in the risk for EAC.”
“Previous studies by R. Upadhyay et al. (2008) have shown that the +61A>G polymorphism was associated with a 1.65 odds ratio for EAC. However, this study extends the earlier observation to show that most of the risk occurs in patients with the G/G variant and in the GERD subset, and that the combination of GERD and a G/G genotype has a significantly increased risk of esophageal cancer,” said, chief of the division of digestive and liver diseases and the Silberberg professor of medicine at Columbia University College of Physicians and Surgeons, New York.
Additional study in larger and more diverse patient groups is necessary to validate the findings; any changes in practice at this time would be premature.
Noted, however, that the current study marks an important step toward developing a test to identify patients at the highest risk of developing esophageal cancer who would benefit from more aggressive screening with esophageal endoscopy.
The University of Toronto, and the Harvard School of Public Health, Boston, analyzed DNA samples from the 584 study participants. The population included 372 people who did not have GERD — 159 cancer patients and 213 healthy controls. There also were 212 people with GERD — most of whom, 150, were cancer patients; only 62 were healthy control, he said.
At baseline, the cancer patients (cases) and controls had similar characteristics except that epidermal growth factor (EGF) gene variants known as A/G or G/G were more common among cases than controls (P = .02) and GERD was more prevalent among cases than controls (P less than .001).
The initial results for the entire study cohort showed that the G/G variant was associated with significantly increased risk of EAC, compared with the normal wild type (A/A) genotype.
Importantly, a stratified analysis then showed that this correlation between the G/G genotype and increased EAC risk only occurred in the subset of patients with GERD. More specifically, the adjusted odds ratio for esophageal adenocarcinoma was 3.39 (P = .005) for the G/G genotype versus the A/A genotype within the GERD subset.
Also within the GERD subset, the odds ratio for esophageal adenocarcinoma was 1.52 for the A/G variant versus the A/A genotype, but this was not statistically significant.
The investigators found that the risk for esophageal adenocarcinoma in those who had the G/G variant increased in tandem with the severity of GERD symptoms experienced. For example, those with G/G variant and GERD symptoms at least once per month had a nearly 10-fold increased risk of esophageal cancer, compared with those who had the A/A genotype and had no GERD symptoms.
Risk was increased approximately 22-fold among those with the G/G variant who experienced GERD symptoms at least once weekly (odds ratio 21.8, P less than .001) or for more than 15 years (OR = 22.4, P less than .001), compared with those who had the A/A genotype and had symptoms less than once monthly or for less than 1 year.
These findings were reflected in the statistical analysis. There was a highly significant interaction between presence of GERD and the G/G genotype (P = .007), and Dr. Cheung and colleagues concluded in their abstract that the “EGF polymorphism exerts its effect on esophageal adenocarcinoma susceptibility through an interaction with GERD.”
Given the high prevalence of GERD, which affects nearly 20 million people in the United States, and the increasing incidence of esophageal cancer in the western world, a test that would help identify those with increased risk of esophageal cancer when it is in earlier and more treatable stages would likely lead to vastly improved outcomes and significant cost savings.
“Performing EGF genotyping for patients with severe or longstanding GERD can help to identify individuals at the greatest risk of esophageal adenocarcinoma.”
“Larger confirmatory studies are needed, but one can imagine the possibility of genetic testing for EGF single nucleotide polymorphisms as part of a future strategy to assess the risk of EAC.”
“In addition, further studies are needed regarding the role of EGFR [EGE receptor] in Barrett’s and esophageal cancer.”