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Mod Pathol. 2018 Jan;31(1):169-178. doi: 10.1038/modpathol.2017.100. Epub 2017 Sep 1.

Anaplastic sarcomas of the kidney are characterized by DICER1 mutations.

Author information

1
Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
2
Department of Cellular Pathology, University Hospital of Wales/Cardiff University School of Medicine, Cardiff, UK.
3
Department of Pathology, Sidra Medical and Research Center, Doha, Qatar.
4
Research Institute of McGill University Health Centre, Montréal, QC, Canada.
5
McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
6
Department of Pathology, Nihon University School of Medicine, Tokyo, Japan.
7
Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
8
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
9
Histology Laboratory, Our Lady's Children's Hospital, Dublin 12, Ireland.
10
Trinity College, University of Dublin, Dublin 2, Ireland.
11
The National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
12
Department of Oncology, McGill University, Segal Cancer Centre, Jewish General Hospital, Lady Davis Institute for Medical Research, Montréal, QC, Canada.
13
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montréal, QC, Canada.

Abstract

Anaplastic sarcoma of the kidney is a rare tumor (≤25 reported cases) characterized by the presence of cysts, and solid areas composed of bundles of undifferentiated spindle cells, showing marked cellular anaplasia (usually accompanied by TP53 overexpression). These tumors often feature prominent areas of cartilage or chondroid material. Germline mutations in DICER1, encoding the microRNA (miRNA) processor DICER1, cause an eponymous syndrome. Recent reports suggest that anaplastic sarcoma of the kidney should be included in DICER1 syndrome as germline DICER1 mutations are associated with the occurrence of such tumors. Therefore, we sought to determine the following: (1) what proportion of anaplastic sarcoma of the kidney have DICER1 mutations; (2) whether the identified mutations affect both alleles of DICER1 (ie, are biallelic); (3) whether somatic missense mutations in the DICER1 RNase IIIb domain impact miRNA generation; and (4) whether TP53 alteration always occurs in these tumors. DICER1 mutations were evaluated by Sanger sequencing and next-generation sequencing in nine tumor/normal pairs. Impact of DICER1 mutations on miRNA generation was evaluated via an in vitro DICER1 cleavage assay. TP53 status was assessed by immunohistochemistry and next-generation sequencing. Eight of the nine cases had at least one RNase IIIb DICER1 mutation that impacted the generation of miRNAs. There were six tumors with truncating DICER1 mutations and in four of them, the mutation found in the tumor was also detected in adjacent normal tissue, and therefore was likely to be either mosaic or germline in origin. Analysis of mutation phase revealed that two of three tumors had biallelic DICER1 mutations. Six of nine anaplastic sarcomas of the kidney had aberrant TP53 immunohistochemisty with damaging TP53 mutations identified in three cases. Taken together, these data suggest that the great majority of anaplastic sarcomas of the kidney have DICER1 mutations and confirm that these tumors are part of the DICER1 syndrome.

PMID:
28862265
DOI:
10.1038/modpathol.2017.100
[Indexed for MEDLINE]
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