The prevalence of DICER1 pathogenic variation in population databases

Jung Kim, Amanda Field, Kris Ann P. Schultz, D. Ashley Hill, Douglas R. Stewart

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

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.

Original languageEnglish
Pages (from-to)2030-2036
Number of pages7
JournalInternational Journal of Cancer
Volume141
Issue number10
DOIs
StatePublished - Nov 15 2017

Keywords

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

Fingerprint

Dive into the research topics of 'The prevalence of DICER1 pathogenic variation in population databases'. Together they form a unique fingerprint.

Cite this