Identification of somatic and germ-line DICER1 mutations in pleuropulmonary blastoma, cystic nephroma and rhabdomyosarcoma tumors within a DICER1 syndrome pedigree

Abstract

Background: DICER1 syndrome is a pediatric cancer predisposition condition causing a variety of tumor types in children and young adults. In this report we studied a family with two relatives presenting a variety of neoplastic conditions at childhood.

Methods: Germ-line mutation screening of the complete coding region of the DICER1 gene in genomic DNA from the proband was performed. The presence of somatic DICER1 mutation and further alterations in driver genes was investigated in genomic DNA obtained from available tumor samples.

Results: A nonsense germ-line mutation in DICER1 causing a truncated protein at the IIIb domain level was identified segregating within a family including two affected relatives who developed in one case cystic nephroma and pleuropulmonary blastoma, and rhabdomyosarcoma and multinodular goiter in the other. Additional in trans DICER1 missense somatic mutations in the IIIb DICER1 domain were found both in the cystic nephroma and in the rhabdomyosarcoma, suggesting that neoplasms in this family might arise from the unusual two-hit mechanism for DICER-derived tumorigenesis in which after the presence of a truncated constitutive protein, a neomorphic DICER1 activity is somatically adquired. Additional genetic alterations, such as TP53 mutations, were identified in the rhabdomyosarcoma.

Conclusions: Besides DICER1 loss of standard activity, oncogenic cooperation of other genes, as mutated TP53, may involve developing higher grade tumors within this syndrome. Given the broad clinical spectrum that may arise, genetic counseling and close surveillance must be offered to all family members at risk of DICER1 syndrome.

Keywords: DICER1 mutations; DICER1 syndrome.

Fig. 1

Morphologic study of the reported tumors. a. Left nephrectomy from the proband. Top: Gross morphology image of the resected kidney presenting a thin-wall multicystic parenchyma. Middle: Medium power view of a haematoxylin and eosin staining (HE) showing multiple cysts of different size. Scarce renal tissue is preserved. Bottom: Higher power view of the cysts surface showing a single layer of flattened/cuboidal cells with well oriented nuclei, acidophilus cytoplasm, and without atypia. b. Left lower lobectomy from the proband. Top: Gross morphology image of the resected lobe. An arrow is pointing to the cystic lesion of 12 mm largest size. Middle: At histological level, a unique benign cystic lesion was identified (HE). Bottom left: A single cubic-cell layer lining the epithelium was observed in most of the cystic lesion. Bottom right: Only very few and isolated clumps of primitive mesenchymal cells and small clusters of cells with rhabdomyomatous differentiation were found along the whole tissue sample. c. Histological images of the rhabdomyosarcoma from the proband’s cousin. Top: HE staining showing dense neoplastic cell proliferation in a solid-storiform pattern. Bottom: Intense pleomorphism is observed, with fusiform-oval cells and common mitotic figures, with focal anaplastic cells

Fig. 2

a. Pedigree of the studied family. Clinical phenotypes are represented with colors. Individuals screened for DICER1 mutations are indicated with + or — if the germ-line mutation was present or absent, respectively. The index patient is marked with an arrow. b. Schematic representation of DICER1 protein structure and corresponding gene exons. Positions of the here identified mutations are indicated. c. Electropherograms corresponding to the germ-line c.5347C > T (p.Q1783*) and somatic c.5425G > A (p.G1809R); c.5428G > C (p.D1810H) mutations