Cleveland Clinic researchers have discovered a new gene associated with Cowden syndrome, an inherited condition that carries high risks of thyroid, breast, and other cancers, and a subset of non-inherited thyroid cancers, as published today in the online version of the American Journal of Human Genetics.
Thyroid cancer, the most common cancer of the endocrine glands, is the fastest rising cancer in women and second fastest rising in men in the U.S. The new gene, SEC23B, discovered by Charis Eng, MD, PhD, Founding Chair of the Genomic Medicine Institute within Cleveland Clinic's Lerner Research Institute and Director of the Center for Personalized Genetic Healthcare, encodes a protein involved in the transport of all proteins within cells.
Dr. Eng and her team started their gene-hunting journey 3 years ago by examining a multi-generational family with early-onset thyroid cancers. They found that all affected family members had inherited a harmful mutation in this gene. The mutation was not found in any unaffected family members.
"This isn't the first time we discovered novel genetic mutations in Cowden syndrome," said Dr. Eng, "but what was truly remarkable is that the SEC23B gene had been identified back in 2009 as the cause of a very rare type of anemia, but not cancer."
In contrast to anemia, where SEC23B function is lost, Dr. Eng and her team discovered that normal thyroid cells expressing mutated SEC23B grew faster, formed larger colonies, invaded more aggressively, and were able to survive in a very stressful microenvironment--all major hallmarks of cancer.
"Our data not only identified a novel cancer-predisposing gene, particularly in thyroid cancer, but also highlighted how cellular stress responses can be hijacked by cancer cells to promote their survival," said Dr. Eng.
Further analyses uncovered that SEC23B mutations are present in up to 3 percent of unrelated Cowden syndrome patients and in 4 percent of patients with non-syndromic thyroid cancer. With up to 50 percent of Cowden syndrome patients testing negative for all known genetic mutations, the syndrome remains an under-diagnosed and difficult-to-recognize condition.
"The discovery of this new cancer-predisposing gene will facilitate predictive genetic testing, risk assessment, genetic counseling, and clinical management of the disease," said Dr. Eng.
Patients with Cowden syndrome develop noncancerous growths, called hamartomas, that can appear on the skin, in mucous membranes and in the intestinal tract. Cowden syndrome predisposes individuals to several types of cancers - an 85 percent lifetime risk of breast cancer, a 35 percent risk for epithelial thyroid cancer, and increased risks of uterine, kidney and colon cancers as well. At least one in 200,000 people are affected by the disease.
Dr. Eng previously discovered that Cowden syndrome is caused by a faulty tumor suppressor gene called PTEN (phosphatase and tensin homolog). The gene has since been implicated in a number of other conditions, including a rare form of autism.
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Dr. Eng is the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and an American Cancer Society (ACS) Clinical Research Professor. This study was funded in part by the National Cancer Institute (P01CA124570 and R01CA118989), American Cancer Society Clinical Research Professorship, Breast Cancer Research Foundation, William Randolph Hearst Foundations, Doris Duke Distinguished Clinical Scientist Award.
Dr. Eng is also the founding Director of the Genomic Medicine Institute's clinical component, the Center for Personalized Genetic Healthcare. Dr. Eng's research interests may be broadly characterized as clinical cancer genetics translational research. For more information visit: http://www.lerner.ccf.org/gmi/eng/ Dr. Eng holds an American Cancer Society Clinical Research Professorship.
About Cleveland Clinic
Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S.News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. More than 3,000 full-time salaried physicians and researchers and 11,000 nurses represent 120 medical specialties and subspecialties. The Cleveland Clinic health system includes a main campus near downtown Cleveland, eight community hospitals, more than 75 Northern Ohio outpatient locations, including 16 full-service Family Health Centers, Cleveland Clinic Florida, the Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, and Cleveland Clinic Abu Dhabi. In 2013, there were 5.5 million outpatient visits throughout the Cleveland Clinic health system and 157,000 hospital admissions. Patients came for treatment from every state and from more than 130 countries. Visit us at http://www.clevelandclinic.org. Follow us at http://www.twitter.com/ClevelandClinic.
About the Lerner Research Institute
The Lerner Research Institute (LRI) is home to Cleveland Clinic's laboratory, translational and clinical research. Its mission is to promote human health by investigating in the laboratory and the clinic the causes of disease and discovering novel approaches to prevention and treatments; to train the next generation of biomedical researchers; and to foster productive collaborations with those providing clinical care. In 2014, LRI researchers published nearly 600 articles in high-impact biomedical journals (top 10% of all biomedical journals). LRI's total annual research expenditure was $255 million in 2014 (with $98 million in competitive federal funding). More than 2,000 people (including approximately 175 principal investigators, 200 postdoctoral fellows, and about 170 graduate students) in 13 departments work in research programs focusing on cardiovascular, cancer, neurologic, musculoskeletal, allergic and immunologic, eye, metabolic, and infectious diseases. The LRI has more than 700,000 square feet of lab, office, and scientific core services space. LRI faculty oversee the curriculum and teach students enrolled in the Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University - training the next generation of physician-scientists. Institute faculty also participate in multiple doctoral programs, including the Molecular Medicine PhD Program, which integrates traditional graduate training with an emphasis on human diseases. The LRI is a significant source of commercial property, generating 66 invention disclosures, 4 licenses, and 50 patents in 2014.
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Journal
American Journal of Human Genetics