Photo by Todd McNaught
Every hour of every day, someone in the United States loses his or her life to oral cancer. Pinpointing the genetic changes associated with the risk and progression of this deadly disease is the goal of a five-year, $4.2 million study lead by Dr. Chu Chen of the Public Health Sciences Division.
Using techniques that permit the simultaneous analysis of thousands of genes, Chen and colleagues at the center and at three local hospitals will identify those that are switched on or off as normal tissue becomes cancerous as well as track the gene-expression changes that occur as patients undergo treatment. Such genetic patterns could be used to predict the aggressiveness of a patient's cancer and ultimately, guide a doctor's choice of therapy based on a patient's expected outcome.
"We know very little about the natural history of the oral cancer," said Chen, a member of the center's Program in Epidemiology. "We'd like to look at progression of the disease and to examine genetic expression patterns to see if those patterns can predict clinical outcome. Based on some of our preliminary evidence, we believe this approach might lead to improved methods for staging oral-cancer tumors, which could help doctors decide whether patients need more or less aggressive treatment."
The genetic profiling-which involves using tools known as DNA microarrays-will be conducted on tissue samples obtained over a five-year period from about 400 patients at the University of Washington, Harborview Medical Center and the VA Puget Sound Health Care System of Seattle who consent to participate in the research. Participants also will complete detailed questionnaires that ask about lifestyle factors and provide information regarding their course of cancer therapy.
Worldwide, about 389,000 new cases of oral cancers-which include tumors of the cheeks, tongue, hard palate, tonsil, or other areas of the mouth-occurred in 2000. About 200,000 die each year from the disease. In the United States, oral cancer will strike about 30,000 people this year; about a third to a half will survive their disease, a rate that has not improved in decades.
Cigarette smoking, chewing tobacco use and alcohol consumption are major risk factors for oral cancer, although the disease can occur in individuals who do not engage in these behaviors. Treatment typically involves surgery to remove the tumor and may be followed by radiation and/or chemotherapy.
Depending on the location of the tumor and its stage, removal of the cancer is often disfiguring and requires reconstructive surgery, Chen said.
"This is a cancer that not only has a high mortality rate, but high morbidity (complications)," she said. "Patients often can't chew, speak or swallow and may need to have bones and teeth removed, particularly if the cancer is advanced."
Currently, doctors gauge a patient's prognosis in part by a tumor's location, thickness and whether the disease has spread to nearby lymph nodes. Such assessments do not provide information about whether tissue immediately outside the tumor boundaries is likely to become cancerous or whether additional treatment after surgery is required.
In pilot studies initiated several years ago, Chen, Dr. Eduardo Mendez, a resident in the Department of Otolaryngology-Head and Neck Surgery at UW, and colleagues demonstrated that gene-expression studies could potentially address these and other clinical questions.
The earlier study, published last year in Cancer, identified hundreds of genes that were differentially turned on or off in normal and oral-cancer tissue. Although there were no significant gene-expression differences between metastatic tumors (those that have spread) and those that were localized, they discovered considerable variation between tumors that had been classified as being of similar stage by conventional clinical assessment, suggesting that non-genetic classification methods may not be adequate to discriminate between cancer subtypes. What's more, their pilot study noted striking similarities in the increase in expression but not the decrease in expression of genes in precancerous and cancerous tissue samples-a finding that could lead to tests for earlier diagnosis of the disease.
Focus and factors
For the new study, Chen and colleagues plan to extend this approach to a larger sample size. Tissue will be obtained each year from 60 patients newly diagnosed with oral cancer who undergo surgery, 10 patients who do not have oral cancer but undergo other oral surgeries and 10 individuals with precancerous lesions. Gene expression analysis of the samples will be correlated with clinical outcomes while taking into account the potential influence of multiple lifestyle factors, treatment choices, and other medical conditions.
"We'll be collecting detailed demographic information, lifestyle habits including alcohol and tobacco use, diet, and use of medications," Chen said. "All of these factors can cause variation among people's genetic profiles."
In addition, the researchers will collect blood samples, mouth rinses and lymph node tissue, if appropriate, for additional genetic studies. Participants with cancer will also be asked for consent to have their course of treatment and health condition tracked over time.
Chen said that because tobacco is a major risk factor for oral cancer, what they learn could prove to be informative for lung and other tobacco-induced cancers.
The National Cancer Institute of the National Institutes of Health funds the study.