DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.
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.
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.
Leslie A
LA
Doros
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.
Christopher T
CT
Rossi
1] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Center for Genetic Medicine Research, Children's Research Institute, Minneapolis, MN, USA.
Jiandong
J
Yang
1] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Center for Genetic Medicine Research, Children's Research Institute, Minneapolis, MN, USA.
Amanda
A
Field
International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
Gretchen M
GM
Williams
International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
Yoav
Y
Messinger
Department of Pathology, Vanderbilt University, Nashville, TN, USA.
Mariana M
MM
Cajaiba
Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Elizabeth J
EJ
Perlman
International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
Kris
K
A Schultz
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
Helen P
HP
Cathro
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
Robin D
RD
Legallo
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
Kristin A
KA
LaFortune
Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kudakwashe R
KR
Chikwava
Pathology Division, Instituto Nacional de Cancer, Rio de Janeiro, Brazil.
Paulo
P
Faria
Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
James I
JI
Geller
Division of Oncology, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
Jeffrey S
JS
Dome
Dana Farber Cancer Institute, Harvard University, Boston, MA, USA.
Elizabeth A
EA
Mullen
Division of Hematology/Oncology, Children's Hospital at Erlanger, University of Tennessee College of Medicine, Chattanooga, TN, USA.
Eric J
EJ
Gratias
1] International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA [2] Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St Louis, MO, USA.
Louis P
LP
Dehner
1] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Center for Genetic Medicine Research, Children's Research Institute, Minneapolis, MN, USA [3] International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA [4] Integrative Systems Biology, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
D Ashley
DA
Hill
D000293:Adolescent; D014408:Biomarkers, Tumor / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D043244:Ribonuclease III / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
D014408:Biomarkers, Tumor; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases