DICER1 in pediatric and adult cancer predisposition populations: prevalence, phenotypes and mosaics.

Purpose: DICER1 tumor predisposition syndrome (DTPS) is a hereditary condition affecting children and young adults. Identification of DICER1 carriers is key for prevention and actionability in families. However, DTPS diagnosis is hindered by its incomplete penetrance and broad phenotypic spectrum.

Methods: We performed an analysis of DICER1 sequencing data from 92 children and 6108 adults with a suspected cancer predisposition syndrome. Clinical and DICER1 somatic data from selected carriers and public datasets were studied.

Results: The prevalence of germline DICER1 PVs was 1:30 in children and 1:3054 in adults. No adult referral phenotype was a known DTPS-associated tumor, although 3/5 carriers developed thyroid alterations. We provide functional evidence supporting the pathogenicity of a novel in-frame deletion. A 56-year-old woman with an ovarian carcinoma and a toxic diffuse thyroid hyperplasia was found to have a postzygotic hotspot missense.

Conclusions: The prevalence of DICER1 PVs in cancer predisposition populations was 5-6 times that reported in the general population. Pediatric-onset DTPS is well characterized, whereas adult carriers mainly present with thyroid abnormalities in the absence of DICER1-related family history, thus requiring accurate criteria for its identification when in constellation with other tumor types. Postzygotic hotspot missenses may exist without the expected severe phenotype.