Identification of a Cowden syndrome patient with a novel PTEN mutation and establishment of patient-derived induced pluripotent stem cells

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, PTENo, was increased in CS-iPSCs, suggesting that it may be the cause of the disease.

Automated summary

This study presents a case of a Japanese woman diagnosed with Cowden syndrome (CS) who had multiple oral polyps, breast cancer, and thyroid cancer. Genetic analysis revealed novel mutations in the PTEN gene, a tumor suppressor gene known to be associated with CS. Further investigation using induced pluripotent stem cells (iPSCs) derived from the patient's blood cells confirmed reduced expression of PTEN transcript, potentially indicating PTENo as the cause for the disease.