The prevalence of germline DICER1 pathogenic variation in cancer populations

Abstract

Background The 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. Methods All datasets were annotated and binned into four categories: pathogenic, likely pathogenic, variant of unknown significance, or likely benign. Results The 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. Conclusion This 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.

Gene of the month:DICER1:ruler and controller

“…19 The most common tumours associated with the DICER1 syndrome are cystic nephroma and pleuropulmonary Gene of the month blastoma (PPB). 20 The initial report of a familial association of these tumours was in 1993 and this involved three siblings, two with cystic nephroma and the third with PPB (figure 2A,B). 21 PPB is the most common paediatric lung neoplasm 22 The tumour develops as multilocular cysts on the surface of the pleura, having aggregates of rhabdomyoblasts and primitive cartilage in the septa (PPB type 1).…”

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype

“…This refined estimate is comparable to the prevalence of germline pathogenic DICER1 variants in The Cancer Genome Atlas (1 in 4600; n = 9173 exomes). 16 It is also comparable to the prevalence of other common genetic disorders, such as fragile X, 26 22q11.2 deletion syndrome, 27 and neurofibromatosis type 1. 28 The discovery, through genome-first approaches, that pathogenic variant prevalence in DICER1 (and in other important tumor-predisposition genes, such as BRCA1 and BRCA2 4 ) is more common than expected has important clinical implications.…”

“…We applied our published scheme with modifications to classify DICER1 variation into 4 categories: pLOF (similar to “pathogenic” by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [ACMG-AMP] criteria), 15 predicted deleterious (similar to “likely pathogenic” by the ACMG-AMP criteria), variant of uncertain significance (VUS), and likely benign (LB). 12 , 16 For statistical analyses, individuals with germline DICER1 pLOF, predicted deleterious, VUS, or LB variants (carriers) were matched to noncarriers (individuals with reference DICER1 sequence) by sex, age, race, and smoking status; for analyses of missense variants, smoking was used as a covariate. CADD 17 and REVEL 18 (bioinformatic variant pathogenicity prediction methods) were also used to investigate the utility of these tools in predicting the consequence of germline DICER1 variation.…”

Phenotypic Similarities Within The Morphologic Spectrum Of DICER1-Associated Sarcomas and Pleuropulmonary Blastoma -- Histopathologic Features Suggesting Genetic Testing and Counselling

“…The DICER1 -tumor predisposition syndrome (OMIM 6012000) is an autosomal dominant disorder with incomplete penetrance and exhibits multiple tumors over time in affected kindreds. [1][2][3][4][5][6] It is characterized by heterozygous germline mutation in DICER1 gene. 4 DICER1 -associated tumors can also be due to biallelic somatic mutations and can be grouped into sarcomas and non-sarcomatous tumors.…”