January 16, 2009 (San Francisco, California) — Specific mutations in the epidermal growth factor (EGF) gene appear to increase the risk for esophageal cancer in patients with gastroesophageal reflux disease (GERD), according to research presented here at the 2009 Gastrointestinal Cancers Symposium. Compared with the EGF wild-type A/A genotype, presence of the G/G variant was associated with an odds ratio (OR) of 1.90 for esophageal cancer, but the correlation between the G/G genotype and esophageal cancer risk was evident only among patients who also had GERD.
"This study shows how GERD symptoms and genes intertwine to increase the risk of esophageal cancer," said Jennifer R. Obel, MD, assistant professor of medicine at the Feinberg School of Medicine, Northwestern University, in Chicago, Illinois, who was not involved in the study. "We've known for many years that GERD patients are at an increased risk of esophageal cancer, but we've never been able to predict how genetic alterations affect this increased risk."
If these findings can be validated, appropriate screening modalities can be offered to high-risk patients, explained Dr. Obel, who moderated a briefing where the data were presented. "It could be used to identify esophageal cancer early, when it is most treatable."
One of the Most Rapidly Growing Cancers
Esophageal adenocarcinoma is one of the most rapidly growing cancers in North America. "Over the last 10 years alone, the annual rate of esophageal cancer has increased dramatically, by about 4-fold, in white males," said lead study author Winson Cheung, MD, clinical research fellow at the University of Toronto, in Ontario. "Similar trends have been seen for Asians and females."
GERD is a common risk factor for esophageal cancer, and affects up to 15% of the adult population in North America, or approximately 20 million people. But not all people with GERD will ultimately develop esophageal cancer, emphasized Dr. Cheung; in fact, only a very small proportion ultimately does.
Single-nucleotide polymorphisms (SNPs) of key genes, such as EGF A61G, have been linked to an elevated risk for esophageal adenocarcinoma. It is been hypothesized that additional genetic factors and/or environmental variables most likely modify the effects of these SNPs on esophageal carcinogenesis.
"Our research group very recently demonstrated that variations in EGF were associated with a 2-fold greater risk of esophageal cancer," said Dr. Cheung. "Environmental factors, such as obesity, alcohol, and dietary factors, have already been shown to be significantly associated with the development esophageal cancer. Chronic GERD is also a factor, and is associated with a 7-fold increase in risk."
In this study, Dr. Cheung and colleagues evaluated whether the association between EGF polymorphism and the development of esophageal adenocarcinoma is altered by the presence of GERD. In a case–control study of 309 patients with esophageal adenocarcinoma and 275 matched healthy controls, the researchers performed EGF genotyping of DNA samples and obtained a GERD history for all participants.
The data were adjusted for confounders, including age, sex, smoking status, pack-years, and adult body mass index. The relation between GERD and genotype was assessed using analyses stratified by GERD history and joint-effects models, which encompassed both the severity and duration of GERD symptoms.
Although baseline characteristics were comparable between patients with esophageal cancer and controls, EGF variants A/G or G/G were more common in cases, as was the prevalence of GERD. Compared with the EGF wild-type A/A genotype, the G/G variant was associated with a higher risk for esophageal cancer (OR, 1.90; P = .007).
Risk for Esophageal Adenocarcinoma by EGF Polymorphism
| Population | Patients/Controls | G/G Variant vs A/A Wildtype: OR |
| Total | 309/275 | 1.9 |
| Without GERD | 159/213 | 0.4 |
| With GERD | 150/62 | 9.7 |
"When we separated those with GERD and those without GERD, the impact of the variant G/G genotype differed," said Dr. Cheung. "For those without significant GERD, the G/G variant was associated with a lower risk, of 0.4, but for those with GERD, the G/G genotype correlated with a substantially higher risk. It was almost 10 times higher, and that was significant."
The correlation between G/G genotype and cancer risk was evident only for the subset of patients with GERD. In addition, the risk for esophageal adenocarcinoma was greatest among patients with the G/G variant who either experienced frequent GERD (more than 1 time per week) or who had experienced GERD symptoms for more than 15 years.
"When we looked at GERD frequency and duration, there was evidence and perhaps even stronger support for the EGF gene and GERD," explained Dr. Cheung. "The risk of esophageal cancer becomes stronger as time goes on and the genotype becomes more abnormal."
For patients with a GERD duration of 15 years or more, the risk for esophageal cancer is 22.4-fold, a very dramatic difference, he pointed out, from the OR of 0.7 in patients who had experienced GERD for less than 1 year.
A similar trend was observed for GERD frequency. Those with the highest frequency of GERD, measured as more than once a week in this study, had a 21.8-fold higher risk for esophageal cancer.
Overall, the researchers found a highly significant interaction between the G/G genotype and the presence of GERD. "It appears that the combination of a specific EFG genotype and GERD history can help to identify individuals with a higher risk of esophageal cancer, and therefore these individuals may benefit most from esophageal screening," said Dr. Cheung.
However, these findings will have to be validated, either prospectively or with larger samples, before changes can be implemented, he concluded.
2009 Gastrointestinal Cancers Symposium (GICS): Abstract 2. Presented January 15, 2009.
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