Patients with Cowden syndrome, a hereditary condition characterized by multiple benign, tumor-like growths called hamartomas, have a heightened risk of developing certain cancers due to their disorder. Cancer in these individuals often arises at a younger age—typically in their 30s or 40s—with breast, thyroid, and uterus being the most common primary sites.
A number of genetic mutations have been identified as being associated with Cowden syndrome, most notably those within the tumor-suppressor gene PTEN. However, recent research showed that only about 25 percent of individuals who met the diagnostic criteria for Cowden syndrome had germline pathogenic PTEN mutations.
Now, a new study, published in the November issue of American Journal of Human Genetics (2015;97:661-676) has shed light on yet another cancer-predisposing gene in Cowden syndrome, SEC23B, which appears to account for a proportion of patients without mutations in PTEN or other known genes.
SEC23B was also found to be associated with apparently sporadic cancers—particularly papillary thyroid cancer—and was linked to a younger age of diagnosis. The findings, the authors noted, have implications for predictive testing, cancer risk assessment, genetic counseling, and clinical management of Cowden syndrome.
“As the years have gone on—it has now been 17 years since the discovery of PTEN—we have found more and more Cowden syndrome patients who had no mutation in the PTEN gene,” said the lead author of the study, Charis Eng, MD, PhD, FACP, ACS Clinical Research Professor, the Sondra J. & Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine, Chairwoman of the Genomic Medicine Institute, and Director of the Center for Personalized Genetic Healthcare at the Cleveland Clinic.
“It turns out that about 75 percent of Cowden patients do not have the PTEN mutation, and although we have found other genes associated with Cowden syndrome, many of them were in the PTEN signaling pathway—so for us to see SEC23B was more of a surprise.”
Eng and her colleagues discovered the first susceptibility gene for Cowden syndrome, the phosphatase and tensin homolog (PTEN) gene, in the late 1990s. In a study of 368 individuals with deleterious germline PTEN mutations, they found elevated lifetime risks for carcinomas of the breast (85.2%), thyroid (35.2%), endometrium (28.2%), colorectum (9.0%), kidney (33.6%), and melanoma (6%) (Nature Genetics 1997;16:64-67).
Because earlier studies used more stringent diagnostic criteria, the proportion of patients with Cowden syndrome that harbored mutations in PTEN once hovered at around 85 percent, Eng noted. But as clinicians began to recognize more subtle features of the disorder, including individuals with characteristics now referred to as Cowden-like, researchers today cite a much lower percentage of patients with classic PTEN mutations.
“Cowden syndrome is a hereditary cancer syndrome associated with the inheritance of deleterious mutations in the PTEN gene,” said another researcher asked for her perspective, Mary B. Daly, MD, PhD, FACP, Chair of Clinical Genetics, the Timothy R. Talbot Jr. Chair for Cancer Research, and Primary Member of the Cancer Prevention and Control Program at Fox Chase Cancer Center—Temple Health.
“Because a large proportion of individuals who meet the clinical criteria for Cowden's syndrome do not actually have mutations in the PTEN gene, there has been a search for additional genes that may cause the same clinical picture.”
For the current study, Eng and her colleagues (first author is Lamis Yehia, PhD) used a combination of whole exome sequencing and family studies—specifically, they started with a single multi-generation, Cowden syndrome-affected family. The family had a history of thyroid cancer in four generations, and three candidate genetic variants were identified from the available DNA of members who met Cowden syndrome diagnostic criteria.
Out of those candidates, the deleterious SEC23B variant was focused on exclusively because of its higher index of pathogenicity, as well as the gene's expression in thyroid, breast, and endometrial normal/cancer tissues.
The researchers then tested an additional 96 Cowden or Cowden-like individuals for the same gene and found deleterious SEC23B variants in three subjects (3.1%), all of whom had papillary thyroid cancer.
The gene was also associated with apparently sporadic cancers, as observed in data analyzed from papillary thyroid (n = 494), breast invasive (n = 222), and uterine corpus endometrioid (n = 156) carcinomas in The Cancer Genome Atlas (TCGA). The highest frequency (4%) was seen in thyroid cancer, and those individuals who tested positive for SEC23B variants tended to have a younger age of diagnosis.
Also asked for his opinion, Ezra Cohen, MD, Professor in the Division of Hematology/Oncology and Associate Director for Translational Science at the University of California, San Diego Moores Cancer Center, said: “For a long time we have realized that there is a hereditary component to thyroid cancer that predisposes individuals and families to this disease. However, there have been few genes identified. This study adds another gene that likely predisposes individuals to thyroid cancer in both familial and sporadic cases.”
Change in Function, Not Loss in Function
Lastly, Eng and her colleagues studied the function of the SEC23B variant and found that the deleterious mutation causes a change in function rather than a loss of function.
SEC23B encodes for a protein that is an essential component of vesicles coated with coat protein complex II (COPII) that serve as transportation for secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex within cells. Functional experiments confirmed that the SEC23B genetic variant found in Cowden and Cowden-like individuals is consistent with carcinogenic activity and favors tumorigenesis even, or especially, under stressful micro-environmental conditions.
“We went on to do functional studies to show that this SEC23B mutation adapted the cells to ER stress,” Eng said. “ER stress can induce apoptosis in cells, but for those with the mutation, the cells seemed to like the ER stress and even became addicted to it.”
Her laboratory will continue to observe patients with Cowden and Cowden-like syndrome and follow them carefully to see how different genetic variants will manifest themselves. For instance, she predicts that those with SEC23B mutations may be more highly predisposed to thyroid cancer, which isn't always the case with other Cowden syndrome susceptibility genes that have been found.
Daly commented: “There are a lot of patients whose family history suggests a hereditary cancer syndrome, but for whom we can't find any of the known mutations. Studies like this will gradually uncover more, mostly rare genes that we can begin to test families for. This will increase their chance of finding something that can guide their risk management and their treatment.”
Also, in normal clinical practice, Eng notes that SEC23B testing will be offered to patients who have Cowden-like features and especially those with thyroid cancer who have tested negative for PTEN and other susceptibility genes.
Not Necessarily Causative
In Cohen's opinion, the methodology and scope of the study are “excellent.” He said he had no real criticisms of the paper, but felt that the main limitation would be that, while the variants in SEC23B were associated with Cowden syndrome and thyroid cancer, the relationship cannot yet be viewed as causative.
More data would be needed to confirm the link: He suggests, for example, delving into the genomics of families with a history of thyroid cancer to see if SEC23B variants occur frequently.