In the developing embryo, the gene NOTCH1 plays a critical role in determining cell fate. Now researchers from Baylor College of Medicine, The University of Texas MD Anderson Cancer Center and Johns Hopkins University School of Medicine have found, for the first time, mutations in Notch1 in cancers of the head and neck.
Not only that, but in these tumors, NOTCH1 seems to act as a tumor suppressor gene – a gene that seeks to protect us from cancer. Mutations halt its anti-tumor activity. In other cancers in which NOTCH1 is mutated, the gene acts as an oncogene – one that promotes cancer.
"This could provide new insights into the mechanisms of transformation of cells (from normal to cancer) and possibly provide new avenues of treatment," said Dr. David Wheeler, associate professor in the Baylor College of Medicine Human Genome Sequencing Center and an author of the report on the sequencing of the exome (the coding region of the genome) for head and neck squamous cell carcinoma that appears online today in Science Express.
Closer to personalized treatment
The discovery of the NOTCH1 mutation and a number of less frequently occurring but significant genetic alterations opens the long-term possibility of tailoring treatment based on the characteristics of each patient's tumor, said Dr. Jeffrey Myers, professor of head and neck surgery at MD Anderson and the paper's senior author.
"Today, we treat head and neck cancer with surgery, radiation and chemotherapy," Myers said. "Our findings will allow us to learn how these mutations affect patients' responses to specific therapies and move us closer to a more personalized approach to treatment."
6th most common form of cancer
Head and neck squamous cell carcinoma, which attacks the lip, mouth, nasal cavity, tongue, pharynx and larynx, is the sixth most common form of cancer in the world with 500,000 new cases identified each year. Wheeler said the National Institute of Dental and Craniofacial Research, which provided funding for the study, helped coordinate the collaboration among institutions. Part of the funding for this study came from the Cancer Prevention Research Institute of Texas.
Treatment, which consists mainly of surgery and radiation, can result in cosmetic deformity and impairment of breathing, speech, swallowing, taste, hear and smell. The five-year survival with this kind of cancer is only about 50 percent. Tobacco use and excess alcohol consumption increase the risk of the disease as well as infection with human papilloma virus, best known for its association with cervical cancer.
In this study, researchers determined the genetic sequence of 18,000 genes that contain the code for the production of proteins in 32 patient tumors that came mainly from MD Anderson and Johns Hopkins. The analysis of the findings found:
- Fewer mutations in tumors associated with human papilloma virus than those without.
- More mutations in tumors of patients who had smoked.
Many of the gene mutations they found were not new, but those in NOTCH1 were, said Wheeler.
"NOTCH1 was the most frequent new mutated gene," he said. The researchers identified 28 NOTCH1 mutations. In seven patients, there were independent mutations in each of the two copies of the gene.
They also found mutations of a gene called FBXW7. NOTCH1 is a target of this gene, which marks it for degradation. NOTCH1 has been previously identified in forms of leukemia, but until recently, its action seemed to be only that of an oncogene – one that activated cancer. The activity of the gene as a tumor suppressor is a new one.
Others who took part in this work from BCM include Kyle Chang, Dr. Lisa Treviño, Jennifer A. Drummond, Donna Muzny, Dr. Yuanqing Wu, and Dr. Richard Gibbs. MD Anderson researchers include Dr. Mitchell J. Frederick, Dr. Curtis R. Pickering, Dr. Tong-Xin Xie, Dr. Jiexin Zhang, Dr. Jing Wang, Dr. Nianxiang Zhang, Dr. Adel K. El-Naggar, Samar A. Jasser, Dr. John N. Weinstein, Dr. Ralph H. Hruban, Dr. William H. Westra, Laura D. Wood and Dr. Jeffrey N. Myers. Johns Hopkins researchers include Drs. Nishant Agrawal, Chetan Bettegowda, Ryan J. Li, Carole Fakhry, Wayne M. Koch, Joseph A. Califano, David Sidransky, Bert Vogelstein, Victor E. Velculescu, Nickolas Papadopoulos and Kenneth W. Kinzler. Califano is also with the Milton J. Dance Head and Neck Center of the Greater Baltimore Medical Center.
Other funding for this study came from the National Institutes of Health, the NIH Specialized Program of Research Excellence, The American Association of Cancer Research Stand Up To Cancer-Dream Team Translational Cancer Research Grant, the Virginia and D.K. Ludwig Fund for Cancer Research and a GlaxoSmithKline Fellowship.