Predisposing Gene Associated With Cowden Syndrome

A new gene has been discovered that is 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.

Cowden syndrome (CS) is an underdiagnosed difficult-to-recognize autosomal-dominant disorder characterized by multiple hamartomas and an increased predisposition to breast, thyroid, endometrial, and other cancers and other non-neoplastic phenotypes that include macrocephaly and mucocutaneous findings.


Scientists at the Cleveland Clinic (Cleveland, OH, USA) and their colleagues subjected germline genomic DNA extracted from peripheral-blood leukocytes of the eligible proband to exome sequencing. Exome enrichment was performed, and subsequent 100 bp paired-end sequencing was performed with a HiSeq 2000 platform (Illumina, San Diego, CA, USA). Mutations in candidate genes of interest were validated by polymerase chain reaction (PCR)-based region-specific mutation analysis through Sanger sequencing. Sequencing was performed in the forward and reverse directions with ABI 3730xl DNA Analyzers (Applied Biosystems, Foster City, CA, USA).

Exome sequencing and targeted genotyping identified Sec23 homolog B, COPII coat complex component (SEC23B) as a candidate gene in a CS-affected family with predominant thyroid cancer. Further analyses uncovered that SEC23B mutations are present in up to 3% of unrelated Cowden syndrome patients and in 4% of patients with non-syndromic thyroid cancer. With up to 50% of Cowden syndrome patients testing negative for all known genetic mutations, the syndrome remains an under-diagnosed and difficult-to-recognize condition.

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% lifetime risk of breast cancer, a 35% 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.

Charis Eng, MD, PhD, the senior author of the study said, “This isn't the first time we discovered novel genetic mutations in Cowden syndrome, 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. 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.” The study was published on October 29, 2105 in the American Journal of Human Genetics.

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