July 20, 2008 Researchers at Rhode Island Hospital have identified two potential molecular markers that may predict outcomes for patients with stomach cancer, one of the most common and fatal cancers worldwide.
According to the study, published in the July 1 issue of Clinical Cancer Research, patients who had poor outcomes following surgery for stomach cancer also had extremely low amounts of two proteins, known as gastrokine 1 and 2 (GKN1 and GKN2), which are produced by normal stomach cells.
The study's findings confirm previous research showing that once stomach cells become cancerous, they manufacture very low amounts of GKN1 and GKN2. However, this is the first known study to link these low protein levels with outcomes following stomach cancer surgery. Researchers say this discovery could eventually help physicians better determine and individualize therapy for stomach cancer, including which patients should be offered chemotherapy and other treatments in addition to surgery.
"Unfortunately, stomach cancer is difficult to cure unless it's discovered early, but because the early stage of the disease has very few symptoms, the cancer is usually advanced by the time it's diagnosed," says lead author Steven Moss, MD, a gastroenterologist with Rhode Island Hospital and an associate professor of medicine at The Warren Alpert Medical School of Brown University.
"That's what makes our findings so significant, because if the potential markers identified in our study can help predict a patient's prognosis, we can decide right away which course of action to take and hopefully help patients live longer and more comfortably," he adds.
According to the National Cancer Institute, approximately 760,000 cases of stomach cancer are diagnosed worldwide each year. Microscopically, stomach cancers can be subdivided into those which appear "diffuse" (a more aggressive form of cancer that can occur throughout the stomach and is more likely to spread) or "intestinal" (resembling the cells normally found only in the small or large intestines). Stomach cancers of both types are often triggered by a chronic infection brought on by Helicobacter pylori (H. pylori), a common bacterium that causes stomach inflammation and ulcers. Surgery is the most common treatment for stomach cancer and can include partial or full removal of the stomach. The five-year relative survival rate of patients with stomach cancer is 24 percent.
Moss, an expert on H.pylori, and colleagues initially set out to learn more about what the bacterium does to normal stomach cells. They focused on GKN1 and GKN2 because these proteins are also suppressed by stomach infections caused by H. pylori.
After looking at tissue samples from more than 150 stomach cancer patients who underwent surgery, the researchers discovered a near total suppression of GKN1 and GKN2 in the majority of patients. This was particularly evident in those patients with the diffuse variant of stomach cancer. More than three-quarters of these patients had extremely low levels of GKN1 and 85 percent had nearly nonexistent levels of GKN2.
Furthermore, in those patients with the intestinal variant of stomach cancer, very low levels of GKN 1 or GKN 2 at the time of surgery were associated with a significantly worse outcome. The median survival was about two years in these patients compared to a survival of more than 10 years for patients with normal levels of GKN1 or GKN2.
Researchers do not yet know the exact function of GKN1 and GKN2. They say further studies are needed to demonstrate the mechanisms responsible for the loss of GKN1 and GKN2 in this patient popoulation as well as the clinical biomarker potential of these two proteins.
The study included tissue samples from 155 patients with stomach cancer (81 men and 74 women) who underwent surgery at Rhode Island Hospital and The Miriam Hospital, both in Providence, R.I. The average age at surgery was 72 years. All four stages of cancer were represented in the study, including 37 patients with Stage I, 44 patients with Stage II, 34 patients with Stage III, and 40 patients with Stage IV. More than 61 patients were being treated for the intestinal variant of stomach cancer while 90 patients had the diffuse variant.
The study was funded by research grants from the National Institutes of Health.
Study co-authors were Murray Resnick, Edmond Sabo, John Gao, Patricia A. Meitner, and Rose Tavares from Rhode Island Hospital and Alpert Medical School; John Rommel and Anna Rubin from Alpert Medical School; Jin-Woo Lee from Inha University Hospital, South Korea; and Bruce R. Westley and Felicity E.B. May from the Northern Institute for Cancer Research at University of Newscastle upon Tyne, United Kingdom.
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