Researchers Identify Gene Variants Linked to Cowden Syndrome, Some Thyroid Cancers

Charis Eng, MD, PhD

Cleveland Clinic researchers have identified novel germline heterozygous gene variants associated with Cowden syndrome and with what had been thought to be spontaneous, non-inherited thyroid cancers.

Cowden syndrome is an inherited condition that carries high risk of thyroid, breast and other cancers. The discovery of previously undescribed cancer-predisposing mutations of the SEC23B gene, reported Oct. 29 in the online version of the American Journal of Human Genetics, could improve predictive testing, cancer risk assessment, genetic counseling and clinical management of Cowden syndrome and thyroid cancer patients.

The unique pathogenic SEC23B variants and their connection with Cowden syndrome and a subset of thyroid cancer cases were found by a team led by Charis Eng, MD, PhD, Chair and founding Director of Cleveland Clinic’s Genomic Medicine Institute and Director of the Center for Personalized Genetic Healthcare.

Dr. Eng and colleagues previously had identified the tumor-suppressor gene PTEN (phosphatase and tensin homolog) as the first susceptibility gene for Cowden syndrome. However, many patients with Cowden syndrome or Cowden syndrome-like clinical features do not have underlying PTEN mutations or large deletions, suggesting that other susceptibility genes also are involved.

In an effort to identify these additional cancer-predisposing genes, in 2012 Dr. Eng and her team began studying a multi-generational family affected by Cowden syndrome and with early-onset thyroid cancer and other cancers. Using genetic sequencing and analysis tools, the researchers found that all affected family members had inherited harmful mutations of SEC23B. The mutations were not found in any unaffected family members.

SEC23B encodes a protein involved in cellular protein trafficking

“This isn’t the first time we discovered novel genetic mutations in Cowden syndrome,” says 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 thyroid cells expressing mutated SEC23B grew faster, formed larger colonies, invaded more aggressively and were able to survive in an extremely stressful microenvironment — all major hallmarks of cancer. Since loss of SEC23B in mice causes endoplasmic reticulum (ER) stress and degradation of cellular secretory organs, the researchers hypothesized that the SEC23B variants might prime mutant cells to respond differently to ER stress triggers. Their findings suggest that the change-of-function SEC23B mutations favor tumorigenesis, perhaps especially in stressful microenvironment conditions.

“Our data highlighted how cellular stress responses can be hijacked by cancer cells to promote their survival,” says Dr. Eng.

Further analyses revealed that SEC23B mutations are present in as many as 3 percent of unrelated Cowden syndrome patients and in 4 percent of patients with non-syndromic thyroid cancer. With as much as 50 percent of Cowden syndrome patients testing negative for all known genetic mutations, the syndrome remains an underdiagnosed and difficult-to-recognize condition. Thyroid cancer is the fastest rising incident cancer in men and second-fastest rising incident cancer in women during the last seven years; hence, the importance of the findings.

“The discovery of these new cancer-predisposing gene variants will facilitate predictive genetic testing, risk assessment, genetic counseling, and clinical management of the disease,” says Dr. Eng.

Patients with Cowden syndrome develop noncancerous hamartomas 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. At least one in 200,000 people is affected by the disease.

Dr. Eng holds the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at Cleveland Clinic and is an American Cancer Society (ACS) Clinical Research Professor. This study was funded in part by the National Cancer Institute, the ACS Clinical Research Professorship, the Breast Cancer Research Foundation, the William Randolph Hearst Foundations and the Doris Duke Distinguished Clinical Scientist Award.