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Int J Cancer. 2017 Nov 15;141(10):2030-2036. doi: 10.1002/ijc.30907. Epub 2017 Aug 21.

The prevalence of DICER1 pathogenic variation in population databases.

Author information

1
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
2
Division of Pathology and Center for Genetic Medicine Research, Children's National Health System, Washington, DC.
3
Cancer and Blood Disorders, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN.
4
International Pleuropulmonary Blastoma Registry, Minneapolis, MN.
5
International Ovarian and Testicular Stromal Tumor Registry, Minneapolis, MN.
6
Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC.

Abstract

The DICER1 syndrome is associated with a variety of rare benign and malignant tumors, including pleuropulmonary blastoma (PPB), cystic nephroma (CN) and Sertoli-Leydig cell tumor (SLCT). The prevalence and penetrance of pathogenic DICER1 variation in the general population is unknown. We examined three publicly-available germline whole exome sequence datasets: Exome Aggregation Consortium (ExAC), 1,000 Genomes (1,000 G) and the Exome Sequencing Project (ESP). To avoid over-estimation of pathogenic DICER1 variation from cancer-associated exomes, we excluded The Cancer Genome Atlas (TCGA) variants from ExAC. All datasets were annotated with snpEff and ANNOVAR and variants were classified into four categories: likely benign (LB), unknown significance (VUS), likely pathogenic (LP), or pathogenic (P). The prevalence of DICER1 P/LP variants was 1:870 to 1:2,529 in ExAC-nonTCGA (53,105 exomes) estimated by metaSVM and REVEL/CADD, respectively. A more stringent prevalence calculation considering only loss-of-function and previously-published pathogenic variants detected in ExAC-nonTCGA, yielded a prevalence of 1:10,600. Despite the rarity of most DICER1 syndrome tumors, pathogenic DICER1 variation is more common than expected. If confirmed, these findings may inform future sequencing-based newborn screening programs for PPB, CN and SLCT, in which early detection improves prognosis.

KEYWORDS:

DICER1; DICER1 syndrome; Sertoli-Leydig cell tumor; pleuropulmonary blastoma; prevalence estimates

PMID:
28748527
PMCID:
PMC5749397
DOI:
10.1002/ijc.30907
[Indexed for MEDLINE]
Free PMC Article

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