Study Uncovers Range of Molecular Alterations in Head and Neck Squamous Cell Carcinomas, New Potential Drug Targets
Investigators with The Cancer Genome Atlas (TCGA) Research Network have discovered genomic differences—with potentially important clinical implications—in human papillomavirus (HPV)-associated head and neck cancers. These findings were reported in Nature.
The researchers also uncovered new smoking-related cancer subtypes and potential new drug targets, and found numerous genomic similarities with other cancer types. Taken together, the study findings may provide more detailed explanations of how HPV infection and smoking play roles in head and neck cancer risk and disease development, and offer potential novel diagnostic and treatment directions.
Rapid Increase in HPV-Associated Head and Neck Cancers
HPV is the most common sexually transmitted virus in the United States, and the number of HPV-associated head and neck cancers has been growing. Almost every sexually active person will acquire HPV at some point in their lives, according to the Centers for Disease Control and Prevention.
The U.S. Food and Drug Administration–approved HPV vaccines should be able to prevent the cancers caused by HPV infection in the head and neck region and elsewhere. However, these vaccines work by preventing new infections, and the long interval between infection and cancer development make it important to understand the molecular changes that bring about these HPV-positive head and neck cancers—as well as those that lead to the HPV-negative cancers—and to develop new approaches for treating them.
“The rapid increase in HPV-related head and neck cancers, noticeably in oropharyngeal tumors, has created an even greater sense of urgency in the field,” said D. Neil Hayes, MD, MPH, senior author of the study and Associate Professor of Medicine at the University of North Carolina (UNC) and the UNC Lineberger Cancer Center. “We’re uncovering differences between tumors with and without HPV infection, and these new data are allowing us to rethink how we approach head and neck cancers.”
Study Details
In the study, researchers performed genomic analyses on 279 head and neck squamous cell carcinomas from untreated patients. Approximately 80% of tumor samples were from individuals who smoked. The majority of samples were oral cavity cancers (61%) and larynx cancers (26%).
While only about 25% of head and neck cancers are linked to HPV infection, TCGA researchers confirmed that many patients with HPV-associated tumors have specific alterations of the gene FGFR3 and mutations in the PIK3CA gene, which are also found in a much broader set of mutations in smoking-related tumors. In contrast, while the EGFR (epidermal growth factor receptor) gene is frequently altered in HPV-negative tumors in smokers, it is rarely abnormal in HPV-positive tumors. Such insights may help in developing potential therapies and biomarkers, noted Dr. Hayes.
Wide Range of Genetic Alterations
Scientists found that more than 70% of head and neck cancers had alterations in genes for growth factor receptors (EGFR, FGFR, IGFR, MET, ERBB2, DDR2), signaling molecules (PIK3CA, HRAS) and cell division regulation (CCND1). These genes may play roles in pathways that control cell growth and proliferation, and for which therapies are either available or in development.
The investigators also discovered new clues about drug resistance in head and neck cancers. They found that genes affecting about 40% of such cancers form key parts of a pathway that helps determine cell survival and drug resistance. They showed that extra copies of the genes FADD and BIRC2, or mutations in or the absence of the CASP8 gene in smoking-related cancers—all of which affect the process of programmed cell death—may underlie the resistance of cancer cells to current treatments. Similarly, the absence of the TRAF3 gene, or extra copies of a gene for the growth-promoting E2F1 protein in HPV-related cancers, may also increase resistance.
'Genomic Map’ of Head and Neck Cancer
The findings showed similarities between head and neck cancer genomes and other cancers, including squamous cell lung and cervical, indicating possible common paths of cancer development, and potential treatment opportunities. “It is surprising to see that head and neck tumor genomes are remarkably similar to cervical and squamous lung cancer genomes. They are from very different organs, but they show similar losses and gains of genetic material across tumors,” Dr. Hayes noted. These common genetic abnormalities belong to a pathway that protects cells from damage and stress.
“These novel findings help establish a genomic map of various head and neck cancers, provide new insights into other similar cancers, and may further our understanding of how viruses can impact disease,” said National Human Genome Research Institute Director Eric D. Green, MD, PhD.
“While many head and neck cancers are preventable, they are increasingly common throughout the world, and often challenging to effectively treat over the long term,” said NCI Director Harold Varmus, MD. “This type of broad analysis provides important new clues for future research and treatment directions.”
Dr. Hayes and Jennifer R. Grandis, MD, are the corresponding authors for the Nature article.
This study was funded by the National Institutes of Health, the Bobby F. Garrett Fund for Head and Neck Cancer Research, and the National Institute on Deafness and other Communication Disorders (NIDCD).
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
