Identification of germlineDICER1mutations and loss of heterozygosity in familial Wilms tumour

Abstract

Wilms tumor (WT), a pediatric renal cancer, is the most common childhood kidney cancer. The etiology of WT is heterogeneous with multiple genes known to result in WT tumorigenesis. However, these genes are rarely associated with familial Wilms tumor (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 4 WT cases. Interestingly, carriers of the DICER1 mutation displayed a greatly increased frequency of WT development compared to the penetrance observed in previously published pedigrees. Also uniquely, in one tumor this DICER1 mutant allele (G803R) was reduced to homozygosity, in contrast to the somatic hotspot mutations typically observed in tumors in DICER1 families.

A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor

“…In the remaining three tumors with two DICER1 mutations, all had RNAse III missense mutations, accompanied by missense mutations of unknown significance in either the PAZ domain, the DEXD/H domain, or a splice site (details in Supplementary Table 3 ). Three additional cases had one missense mutation in the RNAse III domain with high allelic frequencies of this mutation (0.63, 0.75 and 0.97), suggesting loss of heterozygosity at this locus, similar to a previous report [ 13 ]. Therefore, biallelic involvement of DICER1 (either somatic or germline) may be seen in up to 8/651 (1%) of patients with Wilms tumor.…”

“…Sixteen validation patients had 21 DICER1 mutations. Wilms tumors containing two DICER1 mutations have previously been reported [ 12 , 13 ]; therefore, DICER1 mutations were examined in detail within the validation set. Only two validation set patients (one of which was also in the discovery set) had the truncating DICER1 mutations combined with missense mutations in the RNAse III domain described in patients with Pleuropulmonary Blastoma Syndrome [ 14 , 15 ].…”

Familial multinodular goiter and Sertoli-Leydig cell tumors associated with a large intragenic in-frame DICER1 deletion

“…Variations of this model have also been described ( Fig. 3): (a) Germline truncating mutation accompanied by somatic loss of heterozygosity (LOH) has been frequently observed in pineoblastoma, (24) and has also been seen in a Wilms tumor (25) and a pituitary blastoma (14); (b) somatic mosaicism for an RNase IIIb hotspot mutation. In this case, the cells that give rise to a tumor acquire a truncating mutation as the second hit (26,27).…”

New roles for Dicer in the nucleolus and its relevance to cancer

“…While the RNase IIIb domain is a clear hotspot for second-hit mutations in DICER1 tumors, screening of somatic mutations in DICER1 syndromes should not be limited to sequencing this domain as particularly interesting mutations over the rest of the gene have been detected. For example, a RNase IIIa mutation was found in one Wilms tumor, 125 a homozygous G803R mutation (between the DUF283 and PAZ domains) in another Wilms tumor, 117 and a compound mutation with both alleles truncating the protein before the RNase IIIa domain in pineoblastoma. 123 These mutations suggest that the oncogenicity of DICER1 hypomorphic mutants may be more complex than reduction of 5p miRNAs.…”