Abstract
BackgroundThe DICER1 syndrome is an autosomal dominant tumor‐predisposition disorder associated with pleuropulmonary blastoma, a rare pediatric lung cancer. Somatic missense variation in “hotspot” codons in the RNaseIIIb domain (E1705, D1709, G1809, D1810, E1813) is observed in DICER1‐associated tumors. Previously, we found the prevalence of germline pathogenic DICER1 variation in the general population is 1:10,600. In this study, we investigated the prevalence of pathogenic DICER1 germline variation in The Cancer Genome Atlas (TCGA; 32 adult cancer types; 9,173 exomes) and the Therapeutically Applicable Research to Generate Effective Treatment (TARGET; two pediatric cancer types; 175 exomes) cohorts.MethodsAll datasets were annotated and binned into four categories: pathogenic, likely pathogenic, variant of unknown significance, or likely benign.ResultsThe prevalence of DICER1 pathogenic variants was 1:4,600 in TCGA. A single participant with a uterine corpus endometrial carcinoma harbored two pathogenic germline DICER1 (hotspot and splice‐donor) variants, and a single participant with a rectal adenocarcinoma harbored a germline DICER1 stop‐gained variant. In the smaller TARGET dataset, we observed no pathogenic germline variants.ConclusionThis is the largest comprehensive analysis of DICER1 pathogenic variation in adult and pediatric cancer populations using publicly available data. The observation of germline DICER1 variation with uterine corpus endometrial carcinoma merits additional investigation.
Highlights
DICER1 (OMIM 606241) is an RNaseIII endonuclease that is crucial for processing pre‐miRNA into active mature miRNA
The DICER1 syndrome is an autosomal dominant cancer predisposition disorder that arises from pathogenic germline variation in DICER1 and is associated with a variety of benign and malignant tumors, including pleuropulmonary blastoma (PPB), cystic nephroma (CN), Sertoli‐Leydig cell tumors (SLCT), multinodular goiter (MNG), thyroid cancer, rhabdomyosarcoma, and pineoblastoma (Doros et al, 2014; Hill et al, 2009)
In the largest, we found the prevalence of DICER1 pathogenic variation to be ~1/10,600, which was more common than expected (Kim et al, 2017)
Summary
DICER1 (OMIM 606241) is an RNaseIII endonuclease that is crucial for processing pre‐miRNA into active mature miRNA. An unusual variation on Knudson's two‐hit hypothesis is observed in DICER1‐associated tumors: typically, the germline copy is a loss‐of‐function variant and the wild‐type copy is disrupted by a somatic hotspot variant that confers some retained function (Brenneman et al, 2015). We developed a scheme to classify germline DICER1 variation modelled after the joint consensus recommendations of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (Kim, Field, Schultz, Hill, & Stewart, 2017). We applied this approach to germline DICER1 variation from a variety of publicly available exome databases. We apply our published pathogenicity classification and investigate the prevalence of pathogenic germline (and somatic, when available) DICER1 variants in publicly available genome datasets from cancer cohorts
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