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Identification of germline DICER1 mutations and loss of heterozygosity in familial Wilms tumour
  1. Timothy Blake Palculict1,
  2. E Cristy Ruteshouser1,
  3. Yu Fan2,
  4. Wenyi Wang2,
  5. Louise Strong1,
  6. Vicki Huff1
  1. 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  2. 2Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  1. Correspondence to Dr Vicki Huff, The University of Texas MD Anderson Cancer Center, Department of Genetics Unit 1010, 1515 Holcombe Blvd, Houston, TX 77030, USA; vhuff{at}mdanderson.org

Abstract

Wilms tumour (WT), a paediatric renal cancer, is the most common childhood kidney cancer. The aetiology of WT is heterogeneous with multiple genes known to result in WT tumorigenesis. However, these genes are rarely associated with familial Wilms tumour (FWT). To identify mutations predisposing to FWT, we performed whole-genome sequencing using genomic DNA from three affected/obligate carriers in a large WT family, followed by Sanger sequencing of candidate gene mutations in 47 additional WT families to determine their frequency in FWT. As a result, we identified two novel germline DICER1 mutations (G803R and R800Xfs5) co-segregating in two families, thus expanding the number of reported WT families with unique germline DICER1 mutations. The one large family was found to include individuals with multiple DICER1 syndrome phenotypes, including four WT cases. Interestingly, carriers of the DICER1 mutation displayed a greatly increased frequency of WT development compared with the penetrance observed in previously published pedigrees. Also uniquely, in one tumour this DICER1 mutant allele (G803R) was reduced to homozygosity in contrast to the somatic hotspot mutations typically observed in tumours in DICER1 families.

  • Genetics
  • MicroRNA

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