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DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.

Doros LA, Rossi CT, Yang J, Field A, Williams GM, Messinger Y, Cajaiba MM, Perlman EJ, A Schultz K, Cathro HP, Legallo RD, LaFortune KA, Chikwava KR, Faria P, Geller JI, Dome JS, Mullen EA, Gratias EJ, Dehner LP, Hill DA - Mod. Pathol. (2014)

Bottom Line: We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation.Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain.We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Oncology, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.

ABSTRACT
The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

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Unusual Wilms tumor in patient with germline DICER1 mutation and subsequent PPB. (a) Sheets of loose primitive blastemal cells and nodules of cartilage, (b) Primitive cartilage nodule emerging from primitive mesenchyme on left; (c) primitive spindled cells with skeletal muscle differentiation; (d) array of primitive tubules resembling seen primitive tubules in classic Wilms tumor (H&E; original magnification × 200 (a–d).
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fig1: Unusual Wilms tumor in patient with germline DICER1 mutation and subsequent PPB. (a) Sheets of loose primitive blastemal cells and nodules of cartilage, (b) Primitive cartilage nodule emerging from primitive mesenchyme on left; (c) primitive spindled cells with skeletal muscle differentiation; (d) array of primitive tubules resembling seen primitive tubules in classic Wilms tumor (H&E; original magnification × 200 (a–d).

Mentions: The Registry cohort includes four cases of Wilms tumor; one in a child who later developed pleuropulmonary blastoma and the remaining three in relatives of children who had pleuropulmonary blastomas (mother, brother, and great uncle). Of note, the mother with Wilms tumor in childhood did not have a DICER1 mutation, whereas her child with pleuropulmonary blastoma inherited her germline truncating DICER1 mutation from the paternal side. Histologic review of the Wilms tumor from the child who subsequently developed pleuropulmonary blastoma showed an unusual multipatterned neoplasm with blastema, cartilage, differentiated skeletal muscle, anaplasia, and primitive epithelial tubules (Figure 1). Immunohistochemistry for WT1 showed strong nuclear staining in the epithelial components. Next generation sequencing on formalin-fixed, paraffin-embedded tissue from the pleuropulmonary blastoma in this child identified a germline loss of function DICER1 mutation (c.1732dupA; p.Thr578Asnfs*6) and a somatic missense mutation (p.E1813D). Similar analysis of tissue from the Wilms tumor detected the loss of function DICER1 mutation c.1732dupA but did not identify a missense mutation in a common hotspot region. Follow-up Sanger sequencing with small primers designed for hotspot mutation detection was also negative. No slides or DNA were available from the other two Registry cases.


DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.

Doros LA, Rossi CT, Yang J, Field A, Williams GM, Messinger Y, Cajaiba MM, Perlman EJ, A Schultz K, Cathro HP, Legallo RD, LaFortune KA, Chikwava KR, Faria P, Geller JI, Dome JS, Mullen EA, Gratias EJ, Dehner LP, Hill DA - Mod. Pathol. (2014)

Unusual Wilms tumor in patient with germline DICER1 mutation and subsequent PPB. (a) Sheets of loose primitive blastemal cells and nodules of cartilage, (b) Primitive cartilage nodule emerging from primitive mesenchyme on left; (c) primitive spindled cells with skeletal muscle differentiation; (d) array of primitive tubules resembling seen primitive tubules in classic Wilms tumor (H&E; original magnification × 200 (a–d).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117822&req=5

fig1: Unusual Wilms tumor in patient with germline DICER1 mutation and subsequent PPB. (a) Sheets of loose primitive blastemal cells and nodules of cartilage, (b) Primitive cartilage nodule emerging from primitive mesenchyme on left; (c) primitive spindled cells with skeletal muscle differentiation; (d) array of primitive tubules resembling seen primitive tubules in classic Wilms tumor (H&E; original magnification × 200 (a–d).
Mentions: The Registry cohort includes four cases of Wilms tumor; one in a child who later developed pleuropulmonary blastoma and the remaining three in relatives of children who had pleuropulmonary blastomas (mother, brother, and great uncle). Of note, the mother with Wilms tumor in childhood did not have a DICER1 mutation, whereas her child with pleuropulmonary blastoma inherited her germline truncating DICER1 mutation from the paternal side. Histologic review of the Wilms tumor from the child who subsequently developed pleuropulmonary blastoma showed an unusual multipatterned neoplasm with blastema, cartilage, differentiated skeletal muscle, anaplasia, and primitive epithelial tubules (Figure 1). Immunohistochemistry for WT1 showed strong nuclear staining in the epithelial components. Next generation sequencing on formalin-fixed, paraffin-embedded tissue from the pleuropulmonary blastoma in this child identified a germline loss of function DICER1 mutation (c.1732dupA; p.Thr578Asnfs*6) and a somatic missense mutation (p.E1813D). Similar analysis of tissue from the Wilms tumor detected the loss of function DICER1 mutation c.1732dupA but did not identify a missense mutation in a common hotspot region. Follow-up Sanger sequencing with small primers designed for hotspot mutation detection was also negative. No slides or DNA were available from the other two Registry cases.

Bottom Line: We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation.Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain.We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Oncology, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.

ABSTRACT
The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

Show MeSH
Related in: MedlinePlus