Germline pathogenic DROSHA variants are linked to pineoblastoma and Wilms tumor predisposition

Purpose: DROSHA, DGCR8, and DICER1 regulate microRNA biogenesis and are commonly mutated in cancer. Whereas DGCR8 and DICER1 germline pathogenic variants (GPVs) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported. Experimental Design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts. Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma (n=8) or Wilms tumor (WT, n=1). A somatic second hit in DROSHA was detected in all eight tumors analyzed. All pineoblastoma tumors analyzed were classified as miRNA processing altered-1 (PB-miRNA1) subtype. We estimate the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875-1:4,843, but find no evidence for increased adult cancer risk. Conclusions: This is the first report of DROSHA-related tumor predisposition. As pineoblastoma and WT are also associated with DICER1 GPVs, our results suggest the tissues-of-origin for these tumors are uniquely tolerant of general microRNA loss. The PB-miRNA1 pineoblastoma subtype is associated with older age of diagnosis and better outcome than other subtypes, suggesting DROSHA GPV status may have important clinical and prognostic significance. We suggest genetic testing for DROSHA GPVs be considered for patients with pineoblastoma, WT, or other DICER1/DGCR8-related conditions and propose surveillance recommendations through research studies for individuals with DROSHA GPVs.