Abstract 4934: Mosaic RNase IIIb domain DICER1 mutations in children with multiple primary tumors

We describe four children with multiple primary tumours associated with the DICER1 syndrome. Sanger sequencing of constitutional DNA obtained from peripheral blood lymphocytes and/or saliva revealed no likely deleterious germ-line DICER1 mutations. We subsequently sequenced the region encoding the DICER1 RNase IIIa and RNase IIIb domains in gDNA extracted from the tumor samples, and noted the presence of the same RNase IIIb missense mutation in multiple tumors from each patient (Patient A: c.5437G>C; Patient B: c.5125G>A; Patient C: c.5439G>C; Patient D: c.5425G>A). We performed targeted capture followed by deep sequencing on DNA extracted from both normal and tumor tissue, which revealed the presence of the respective RNase IIIb mutations in a low percentage of sequencing reads (0.2 - 13%) in constitutional DNA from three of the four patients (Patients A, B and C). The relative abundance of the allele harboring the DICER1 RNase IIIb mutation was significantly higher in the tumors compared to normal tissue from the surrounding organ and/or distant sites. Taken together, these findings indicate a mosaic origin of the DICER1 RNase IIIb missense mutations. The mosaic origin of Patient D's mutation remains to be unequivocally established.We further hypothesized that, in the setting of a mosaic DICER1 RNase IIIb mutations, we might discover second somatic mutations outside of the RNase IIIb domain which initiate two-hit tumorigenesis as seen in most DICER1-related tumors. Sequenci...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Biology Source Type: research