Background Cowden syndrome (CS) is an autosomal dominant disorder characterised by macrocephaly, specific mucocutaneous features and predisposition to benign and malignant tumours. Detectable mutations in the PTEN gene account for 80–85% of cases.
Methods/Results Here, the authors report a patient with macrocephaly and typical CS mucocutaneous features who developed dysplastic cerebellar gangliocytoma and two synchronous thyroid cancers of papillary and oncocytic type, in whom a germline 500-Kb deletion on chromosome 10q23 including PTEN was detected. Molecular characterisation of thyroid cancer led to the identification of the oncogenic BRAFV600E mutation in the papillary carcinoma. BRAFV600E has been proposed to cause cancer only in the presence of a tumour-suppressor mutation, which, in this case, could be the PTEN deletion. In the oncocytic carcinoma, a large deletion in the mitochondrial-DNA-encoded MTND1 was found, associated with respiratory complex I disassembly, which was subsequently shown to be a constitutional, de novo genetic lesion.
Conclusions This is the first reported case of a patient with CS carrying constitutional deletions in both the nuclear and the mitochondrial genome that might help elucidate some aspects of CS pathogenesis.
- Cowden syndrome
- PTEN protein
- mitochondrial DNA
- cell biology
- clinical genetics
- copy number
- molecular genetics
- cancer: breast
- cancer: colon
- thyroid disease
- cancer: endocrine
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Funding Funding for this study was provided by the Italian Ministry of University and Research, Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health. GG was supported by the Italian Ministry of University and Research through a grant FIRB (Fondo per gli Investimenti della Ricerca di Base) Associazione Italiana per la Ricerca sul Cancro funded reagents and the Italian Ministry of Health supported staff involved in genetic counselling and testing through a grant in the framework of PIO5 (Progetto Integrato Oncologia 5).
Competing interests None.
Patient consent Obtained.
Ethics approval Clinical assessment and genetic testing in this family were performed primarily for diagnostic purposes. Genetic counselling and testing were carried out in agreement with the European guidelines. All the involved subjects gave their informed consent to diagnostic genetic testing and to additional analyses needed to obtain insights on disease aetiology and pathogenesis. The consent form for genetic tests that they signed had been previously approved by the Ethical and Legal Board of the Policlinico S.Orsola-Malpighi.
Provenance and peer review Not commissioned; externally peer reviewed.