A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case reportReport as inadecuate




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Reference: Barnes, DJ, Hookway, E, Athanasou, N et al., (2016). A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report. BMC Cancer, 16 (1), Article: 629.Citable link to this page:

 

A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report

Abstract: Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula.A 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16(INK4A), D74A). SNP-array CGH on DNA samples revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators.In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case.

Publication status:PublishedPeer Review status:Peer reviewedVersion:Publisher's version Funder: National Institute for Health Research   Notes:Copyright © 2016 The Authors. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Bibliographic Details

Publisher: BioMed Central

Publisher Website: https://www.biomedcentral.com/

Journal: BMC Cancersee more from them

Publication Website: https://bmccancer.biomedcentral.com/

Volume: 16

Issue: 1

Extent: Article: 629

Issue Date: 12 August 2016

pages:Article: 629Identifiers

Doi: https://doi.org/10.1186/s12885-016-2669-3

Issn: 1471-2407

Uuid: uuid:c67e0dc2-dac7-43f3-86cc-71336c050ae0

Urn: uri:c67e0dc2-dac7-43f3-86cc-71336c050ae0

Pubs-id: pubs:639105 Item Description

Type: journal-article;

Language: eng

Version: Publisher's versionKeywords: germline CDKN2A mutation melanotic Neuroectodermal Tumor of Infancy RNA-Seq RPLP1-C19MC fusion gene sensitivity to lysine demethylase inhibitors

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Author: Barnes, DJ - Oxford, MSD, NDORMS - - - Hookway, E - Oxford, MSD, NDORMS - - - Athanasou, N - - - Kashima, T - - - Oppermann, U -

Source: https://ora.ox.ac.uk/objects/uuid:c67e0dc2-dac7-43f3-86cc-71336c050ae0



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