Abstract
Cowden syndrome (CS) is an autosomal dominant inherited disorder characterized by multiple hamartomas in various organs such as the mucosa, skin, and gastrointestinal tract. Patients with CS are at high risk for breast and thyroid cancers. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that negatively regulates the AKT pathway, and PTEN mutations are known to be the major causes of this syndrome. However, the pathogenesis of this syndrome has not been clarified. Here, we present a case of a Japanese woman with multiple oral polyps, breast cancer, and thyroid cancer who was clinically diagnosed with CS. We obtained DNA and RNA samples from the patient’s peripheral blood mononuclear cells (PBMCs) and buccal mucosa tumor. Next-generation sequencing revealed novel germline mutations (c.1020delT and c.1026G > A) in exon 8 of PTEN. Sanger sequencing identified no PTEN transcript from the mutant allele. Furthermore, CS-specific induced pluripotent stem cells (CS-iPSCs) were established from PBMCs of the patient under feeder- and serum-free culture. Compared with healthy PBMCs and iPSCs, both of the CS-derived PBMCs and CS-iPSCs exhibited significantly reduced expression of the PTEN transcript. The transcriptional variant, PTENδ, was increased in CS-iPSCs, suggesting that it may be the cause of the disease.
Highlights
Cowden syndrome (CS) (MIM 158,350) is a disease that causes hamartoma neoplasms in multiple organs, including the skin, mucous membranes, and gastrointestinal tract (Eng, 1997)
We have previously reported the induction of induced pluripotent stem cells (iPSCs) from dental pulp and peripheral blood mononuclear cells (PBMCs) of patients with several genetic disorders under feeder, serum-free culture conditions (Yamasaki et al, 2014; Hamada et al, 2020a, 2020b)
Novel PTEN genetic mutations were detected by next‐generation sequencing (NGS) analysis NGS analysis revealed a deletion of base position 1020 T and a mutation of base position 1026 G to A in the coding sequence of the PTEN gene (Fig. 1A)
Summary
Cowden syndrome (CS) (MIM 158,350) is a disease that causes hamartoma neoplasms in multiple organs, including the skin, mucous membranes, and gastrointestinal tract (Eng, 1997). It is a rare autosomal dominant genetic disorder that occurs in 1 per 250,000 people. Throughout their lifetime, CS patients have an increased risk of developing breast and thyroid cancer, 50–85% and 30–40%, respectively (Tan et al, 2012). It is known that most cases of CS result from a mutant phosphatase and tensin homolog deleted on chromosome 10 (PTEN) allele (MIM 601,728) (Eng, 2000). Since there are few studies on the relationship between PTEN mutations and the phenotype of CS, the pathogenesis of this disease remains unclear
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