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

in Clinical cancer research : an official journal of the American Association for Cancer Research by Peter N Fiorica, Lisa Golmard, Jung Kim, Riyue Bao, Frank Y Lin, Angshumoy Roy, Allison Pribnow, Melissa R Perrino, Julien Masliah-Planchon, Sophie Michalak-Provost, Jennifer Wong, Mathilde Filser, Dominique Stoppa-Lyonnet, Franck Bourdeaut, Afane Brahimi, Olivier Ingster, Giselle Saulnier Sholler, Sarah A Jackson, Mark M Sasaki, Trent Fowler, Anita Ng, Ryan J Corbett, Rebecca S Kaufman, Jeremy S Haley, David J Carey, Kuan-Lin Huang, Sharon J Diskin, Jo Lynne Rokita, Hussam Al-Kateb, Rose B McGee, Joshua D Schiffman, Kenneth S Chen, Douglas R Stewart, D Williams Parsons, Sharon E Plon, Kris Ann P Schultz, Kenan Onel

TLDR

  • DROSHA pathogenic variants are associated with an increased risk of developing pineoblastoma and Wilms tumor in children.
  • The population prevalence of DROSHA loss-of-function variants is estimated to be 1:3,875-1:4,843, and these variants do not appear to be associated with increased adult cancer risk.
  • Genetic testing and surveillance recommendations may be necessary for individuals with DROSHA GPVs.

Abstract

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. 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. 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. 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.

Overview

  • The study investigated the association between germline DROSHA pathogenic variants (GPVs) and cancer risk and clinical phenotypes.
  • The study analyzed germline and tumor samples from patients with pineoblastoma and Wilms tumor to identify DROSHA GPVs and their relationship to second hits in tumors.
  • The study aimed to determine the population prevalence of germline DROSHA loss-of-function variants and to explore their potential relationship to cancer risk and clinical phenotypes.

Comparative Analysis & Findings

  • The study identified nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma or Wilms tumor.
  • A somatic second hit in DROSHA was detected in all eight tumors analyzed, suggesting that DROSHA GPVs increase the risk of developing these tumors.
  • The study estimated the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875-1:4,843, but did not find evidence for increased adult cancer risk.

Implications and Future Directions

  • The study suggests that genetic testing for DROSHA GPVs may be warranted for patients with pineoblastoma, Wilms tumor, or other DICER1/DGCR8-related conditions.
  • Surveillance recommendations may be necessary for individuals with DROSHA GPVs, and further research is needed to determine the optimal monitoring strategy.
  • The study's findings also propose that the PB-miRNA1 pineoblastoma subtype, which is associated with older age of diagnosis and better outcome, may have important clinical and prognostic significance.
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