The studies were led by researchers from the Broad Institute of MIT and Harvard, the University of Pittsburgh Cancer Institute, the Johns Hopkins Kimmel Cancer Center, and the University of Texas M. D. Anderson Cancer Center.
Tobacco use, excessive alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for HNSCC, which includes cancers arising in the mouth and throat. The 5-year survival rate for many types of HNSCC has improved little over the past 40 years.
To search for gene defects, or mutations, that may play a role in HNSCC, the researchers compared whole-exome sequences of tumor tissue with those of matched normal tissue from the same patients. Both research teams confirmed genetic abnormalities that were previously implicated in HNSCC, including mutations in the TP53 tumor suppressor gene, which were by far the most common.
The two teams also identified a large number of unexpected gene mutations in HNSCC, most notably in the NOTCH1 gene and other genes involved in squamous cell differentiation—the process by which less mature, rapidly dividing cells develop into more specialized squamous cells that divide more slowly.
“The degree of differentiation—that is, tumor cell grade—has never consistently been shown to be a clinical prognostic factor” in HNSCC, said Dr. Jennifer Grandis of the University of Pittsburgh, a senior author of one of the studies. “So it was surprising to find mutations in a series of genes that…appear to contribute to differentiation.”
Both studies found far fewer mutated genes in HPV-positive tumors than in HPV-negative tumors, supporting the idea that HPV-positive HNSCC, which has a better prognosis, is a distinct disease and thus merits different treatment.
The results of multidisciplinary collaborations such as these “will allow us for the first time to understand the complex biology of head and neck cancer,” Dr. Grandis said. “It’s clearly not one disease. It’s many diseases, despite appearing identical under the microscope.
“It’s right to be cautiously pessimistic,” Dr. Grandis said. But she believes that delving into the biological complexity of cancers such as HNSCC will ultimately reveal new therapeutic targets.
“We’re still in just the baby steps of these genetic findings,” she continued. The most important next step, she explained, is to identify the subset of mutations that drive tumor formation and figure out how to target them. “These are the patients’ tumors—they are speaking to us. Whether we understand what they say is a different question.”
Also in the Journals: Key Genetic Mutations Found in One Type of Brain Cancer
Researchers have identified mutations in two genes that may play a critical role in the development of oligodendroglioma, the second-most-common type of brain cancer in adults.
In the study, published online August 4 in Science, Dr. Chettan Bettegowda and his colleagues at the Johns Hopkins University Kimmel Cancer Center sequenced the exomes, or protein-coding portions of DNA, in seven oligodendroglioma tumors and found that two genes, CIC and FUBP1, were frequently mutated. The researchers then performed exome sequencing on 27 additional oligodendroglioma samples and again found that both genes were frequently mutated. The genes had a mutational pattern that is consistent with those commonly seen in tumor suppressor genes, the researchers reported.
“Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor,” said study co-author Dr. Nickolas Papadopoulos in a news release.
According to Dr. Bettegowda, further research is needed to determine whether the genes’ mutational status can be used to guide prognosis and whether the genes can be targets for therapy.
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