New study of tumor genetics may help to treat patients with head and neck cancer

May 19 2004

Head and neck tumors account for more than 40,000 new cancers annually in the United States. The most common of these is squamous cell carcinoma. Prognosis is based largely on location and size of the tumor, and if the cancer has spread, or metastasized, to lymph nodes and distant sites in the body.

The study identified four tumor gene expression patterns that may serve as biomarkers of prognosis, including tumor recurrence or metastasis, for patients with head and neck squamous cell cancer and for whom aggressive therapy might be best.

Dr. Charles M. Perou, assistant professor of genetics and pathology and laboratory medicine at the University of North Carolina at Chapel Hill School of Medicine, led the study.

Writing in the May 18 issue of the journal Cancer Cell, Perou, also a member of the UNC Lineberger Comprehensive Cancer Center, and colleagues from UNC and Vanderbilt University presented their findings based on the gene expression patterns of 60 head and neck tumor samples that were assayed using DNA microarrays, a technology Perou pioneered. The samples came from patients at UNC Hospitals.

"This technology allows us to determine the expression level of tens of thousands of genes at once," Perou said. "What excites me about gene expression profiling is that it allows us to study real human tumor samples and collect thousands of data points which we could not do before. There is no animal model system here. We're studying the disease as people have it."

Gene expression refers to the transcription of the information contained within DNA, the repository of genetic information, into messenger RNA (mRNA) molecules that are then translated into the proteins that perform most of the cells' critical functions.

Scientists then study the kinds and amounts of mRNA produced by a cell to learn which genes are expressed, which in turn provides insights into how the cell responds to its changing needs.

A microarray is a tool for analyzing gene expression that consists of a small membrane or glass slide containing samples of many genes arranged in a regular pattern. It works by exploiting the ability of a given mRNA molecule to bind specifically to, or hybridize to, the DNA template from which it originated. By using an array containing many DNA samples, scientists can determine, in a single experiment, the expression levels of hundreds or thousands of genes within a cell by measuring the amount of mRNA bound to each site on the array.

With the aid of a computer, and the use of fluorescent "tags," the amount of mRNA bound to the spots on the microarray can be visualized and precisely measured, generating a profile of gene expression in the cell.

The four subtypes showed statistically significant differences in recurrence-free survival during a 16-month period, the report said.

One subtype was associated with the worst outcome; this subtype "shows an epidermal growth factor pathway activation signal, and that's potentially important because there are many new drugs in the clinic today that target that pathway," Perou said.

Another subtype was associated with a "tobacco exposure signature," showing a high expression of genes involved in response to tobacco. Nearly all tumor samples in this subtype came from smokers.

"Another research group did a microarray study comparing airway epithelial samples from smokers versus nonsmokers and said that these genes were high in the smokers and low in the nonsmokers," Perou said.

"And we picked up that exact same set of genes in our study, a validation of what both groups have found."

The study also found tumor molecular biology that differentiated patients with lymph node metastasis from those without metastasis.

"We can see a signature in tumor cells that indicate they are likely to metastasize and the converse, that they are less likely to do so," Perou said.

"This is preliminary data. It must go through rigorous testing and validation before it can change treatment," he added.

"Gene arrays are already providing valuable and useful biological and clinical information and in a handful of years will probably become diagnostic tools in addition to the spectacular biology tools they already are."

Lead author of this study was Dr. Christine H. Chung, a former medical fellow at UNC, now a medical oncologist at Vanderbilt University.

Support for the research came from UNC Lineberger Comprehensive Cancer Center and from the National Cancer Institute.