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The Lancet Oncology

Wednesday, January 21, 2009

Mutations in EGF Gene Associated with Increased Esophageal Cancer Risk

Researchers have identified specific mutations in the epidermal growth factor (EGF) gene that are associated with increased esophageal cancer risk in people with gastroesophageal reflux disease (GERD). This is the first study to examine EGF mutations as predictors of esophageal cancer risk in patients with GERD.

The results of this study were presented during the sixth annual Gastrointestinal Cancers Symposium , which is co-sponsored by the American Gastroenterological Association (AGA) Institute , the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO) and the Society of Surgical Oncology (SSO), being held in San Francisco, CA (January 15 – 17, 2009).

‘We’ve known for some time that GERD is a risk factor for esophageal cancer, but our findings are the first to identify specific genetic markers that are linked with increased cancer risk in patients with GERD,’ said Winson Y. Cheung, MD, a clinical research fellow working with the University of Toronto and the Harvard School of Public Health, and the lead author of the study.

‘While our findings will need to be validated in larger and more diverse patient groups, this is a first step in the right direction toward developing a test to identify which patients are at highest risk of esophageal cancer and would benefit from more aggressive screening. And because GERD is a common condition, the ability to single out patients at high risk of cancer could lead to better outcomes and significant cost savings.’

Incidence and cause of GERD
Gastroesophageal reflux disease (GERD), also referred to as heartburn, is reflux and regurgitation of the contents of the stomach into the esophagus. The disease is quite common, can affect everyone, from newborn infants to adults, and is often frequent and severe enough to impact daily life. In the United States it is estimated that nearly 60 million people experience symptoms at least once a month. Over 60% of the elderly have frequent GERD, and over 14 million Americans have GERD so frequently and severely that they experience symptoms every single day.

In general, the presence of gastroesophageal reflux implies lower esophageal sphincter (LES) incompetence. Located at the very bottom of the esophagus, where the esophagus joins the top of the stomach, the esophageal sphincter is a ‘high pressure zone’ between the esophagus and stomach. After swallowing, food moves down the esophagus by esophageal contraction. Then esophageal sphincter relaxes to allow food to pass into the stomach, and then closes again to prevent reflux of the stomach content, including food and digestive juices, back into the esophagus. Another important contributor to GERD is the failure of the antireflux barrier (ARB) and its primary component, the gastroesophageal valve (GEV).

Although the lower esophageal sphincter plays a major role in the occurrence of GERD, researchers recently started to focus more on the gastroesophageal valve as the largest contributor to the anti-reflux barrier. In healthy individuals, the Angle of His, the angle at which the esophagus enters the stomach, is intact creating a valve that prevents duodenal bile, enzymes, and stomach acid from traveling back into the esophagus where it can cause burning and inflammation of the sensitive esophageal tissue. In gastroesophageal reflux disease, the ‘valve’ is damaged, weakened or absent. This causes the acidic digestive juices from the stomach to flow back (or reflux) into the esophagus. This often creates a burning pain in the center of the chest that starts in the upper abdomen and sometimes spreads into the neck.

There are a number of factors contributing to the development of GIRD. These may include weight gain, fatty foods, caffeinated or carbonated beverages, alcohol, tobacco smoking, and drugs, including anticholinergics, antihistamines, tricyclic antidepressants, Ca channel blockers, progesterone, and nitrates.

In severe or chronic GERD, regurgitation occurs regularly, spilling acid, bile, and other stomach contents not only into the esophagus but also into the lungs, mouth, pharynx and even the nose. This can lead to a variety of complications including esophagitis, anemia, esophageal stricture, peptic esophageal ulcer, and Barrett's esophagus, a condition that develops in the lining of the lower esophagus.

Uncontrolled regurgitation has also been associated with a number of atypical symptoms, including a chronic sore throat, cough, laryngitis, dental erosions, discomfort in the ears and nose, recurrent bronchitis, asthma like symptoms and sleep disturbance. Cell damage of the lower part of the esophagus has been linked to the development of esophageal adenocarcinoma.

Given the number of symptoms and the potential for severe complications, GERD has a significant impact on quality of life and, in extreme cases, life expectancy.
Treatment may include a combination of lifestyle changes (including weight loss), over the counter medications (OTC), and prescription drug regimens, and, in more severe cases, surgery.

Esophageal Cancer
According to the American Cancer Society, about 30 percent of esophageal cancers can be traced to GERD. In 2008, more than 16,000 cases of esophageal cancer were diagnosed. This disease is 3 to 4 times more common among men than among women and about 50% more common among African Americans than among caucasians. Nevertheless, if detected early, the disease is generally curable.

Because esophageal cancer is usually diagnosed at a relatively late stage, it is one of the most deadly forms of gastrointestinal cancer. With a mortality rate exceeding 85%, most patients will eventually die of the disease. However, statistics from the American Cancer Society show that survival rates have been improving. During the early 1960s, only 4% of all white patients and 1% of all African-American patients survived at least 5 years after diagnosis. Today, about 18% of Caucasian, and 11% of African-American patients survive at least 5 years after diagnosis.

Early detection is the best prevention. But screening is invasive and expensive, and therefore not recommended for all patients with GERD. The American College of Gastroenterology therefore recommends periodic endoscopies only for patients with long-standing symptoms of reflux.

Esophageal carcinogenesis involves multiple genetic alterations. In this study, Cheung and his team of researchers collected DNA samples from 309 patients being treated for esophageal adenocarcinoma (the most common type of esophageal cancer in North America) at Massachusetts General Hospital in Boston, and 275 healthy, matched controls. The investigators analyzed study participants’ genotypes and GERD history.

Baseline characteristics were comparable between cases and controls except that epidermal growth factor (EGF) variants (A/G or G/G) were more common (p=0.02) and GERD was more prevalent (p<0.001)epidermal growth factor (EGF) called G/G who experienced symptoms associated with GERD more than once a month, compared with those who had the A/A (normal, or wild-type) variant epidermal growth factor (EGF) without GERD, were at a 10-fold increased risk of esophageal cancer (OR 1.90; 95% CI, 1.2-3.0; p=0.007).

Stratified analyses revealed that this correlation between G/G genotype and esophageal cancer risk was evident only for the subset of patients with GERD. The researchers noted that the risk of esophageal cancer increased further among patients with the mutation who suffered from GERD more frequently, generally more than 1 time per week (OR 21.8; 95% CI, 5.1-94.0; p<0.001), p="0.007)or for more than 15 years (OR 22.4; 95% CI, 6.5-77.6; p<0.001).

The study showed a highly significant interaction between the G/G genotype and the presence of GERD (p=0.007).

Patients with GERD and the genetic variant called A/G had an intermediate increase in risk.

While researchers concluded that performing EGF genotyping for patients with severe or longstanding GERD can help to identify individuals at the greatest risk of esophageal adenocarcinoma, the results of this test are just one step that may lead to the development of new tests for finding esophageal cancer at an earlier, more curable stage.

Better understanding of the genetic predisposition may eventually lead to new therapies that repair the abnormal genetic changes in esophageal cancer cells.

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