Abstract
Ovarian fibrosarcomas are extremely rare tumors with little genomic information available to date. In the present report we present the tumoral exome and transcriptome and the germinal exome of an ovarian fibrosarcoma from a 9-years old child. We found a paucity of mutations (0.77/Mb) and CNV alterations. Of these, the most relevant were a point mutation in the metal-binding site of the microRNA-processing DICER1 enzyme and a frame-shift alteration in the tumor suppressor gene NF1. We validated a germinal truncating mutation in DICER1, which was consistent with a DICER1 Syndrome diagnosis, providing the first example of an ovarian fibrosarcoma as the presenting neoplasia in this syndrome. Network and enrichment analyses showed that both a mesenchymal signature and a Hedgehog cascade could be driving the progression of this tumor. We were also able to find a global lincRNA deregulation, as the number of lincRNAs transcripts expressed in the tumor was decreased, with a concomitant upregulation of previously described non-coding transcripts associated with cancer, such as MALAT1, MIR181A1HG, CASC1, XIST and FENDRR. DICER1 Syndrome should be considered as a possible diagnosis in children ovarian fibrosarcoma. The role of lncRNAs in neoplasias associated with DICER1 alterations need to be studied in more detail.
Highlights
Ovarian fibrosarcomas are rare and aggressive tumors
A 9-year-old girl, without significant pathologic antecedents, received a diagnosis of an ovarian fibrosarcoma supported by morphology (Fig. 1A–C), and a positive immunohistochemistry staining for vimentin (100% positive cells) and negative for inhibin (Fig. 1D,E)
We report the genomic characterization of a fibrosarcoma arising from the ovary of a 9 years-old child
Summary
Ovarian fibrosarcomas are rare and aggressive tumors. These sex cord-stromal neoplasias are derived from the stromal component of the ovary and give rise to large, highly vascular and mitotically-active tumors. Germline truncating mutations in the microRNA-processing protein DICER1 gene have been reported in patients with pleuropulmonary blastoma (PPB) or the related familiar DICER1 syndrome which includes, besides PPB, cystic nephroma, Sertoli-Leydig cell tumors, medulloepitheliomas and embryonal rhabdomyosarcomas[6]. Patients with DICER syndrome would make primitive cells susceptible to oncogenesis by a second mutation in a RNAse IIIb “hotspot”, altering microRNA processing[10]. Due to their rarity, there are no deep characterizations of the molecular alterations in these ovarian fibrosarcomas. We present the first genomic report of this rare neoplasia from a 9-years old child and provide evidence that this neoplasia needs to be added as a presentation tumor in DICER1 syndrome patients, supporting an oncogenic role for this gene
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