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Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53
Since the introduction of next-generation sequencing, the frequency of germline pathogenic TP53 variants and the number of cases with unusual clinical presentations have been increasing. This has led to the expansion of the classical Li–Fraumeni syndrome concept to a wider cancer predisposition synd...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995879/ https://www.ncbi.nlm.nih.gov/pubmed/35419288 http://dx.doi.org/10.3389/fonc.2022.849004 |
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author | Butz, Henriett Lövey, József Szentkereszty, Márton Bozsik, Anikó Tóth, Erika Patócs, Attila |
author_facet | Butz, Henriett Lövey, József Szentkereszty, Márton Bozsik, Anikó Tóth, Erika Patócs, Attila |
author_sort | Butz, Henriett |
collection | PubMed |
description | Since the introduction of next-generation sequencing, the frequency of germline pathogenic TP53 variants and the number of cases with unusual clinical presentations have been increasing. This has led to the expansion of the classical Li–Fraumeni syndrome concept to a wider cancer predisposition syndrome designated as the Li–Fraumeni spectrum. Here, we present a case with a malignant, metastatic perivascular epithelioid cell tumor (PEComa) of the thigh muscle and a sinonasal carcinoma harboring a novel TP53 germline splice mutation (NM_000546.5:c.97-2A>C). The classical presentation of LFS in the long-since deceased mother and the presence of a germline TP53 variant in the proband suggested a possible familial TP53-related condition. Complex pathological, molecular, and clinical genetic analyses (whole exome sequencing of germline variants, multigene panel sequencing of tumor DNA, Sanger validation, an in vitro functional test on splicing effect, 3D protein modeling, p53 immunohistochemistry, and pedigree analysis) were performed. The in vitro characterization of the splice mutation supported the pathogenic effect that resulted in exon skipping. A locus-specific loss of heterozygosity in the PEComa but not in the sinonasal carcinoma was identified, suggesting the causative role of the splice mutation in the PEComa pathogenesis, because we excluded known pathogenetic pathways characteristic to PEComas (TSC1/2, TFE3, RAD51B). However, the second hit affecting TP53 in the molecular pathogenesis of the sinonasal carcinoma was not identified. Although PEComa has been reported previously in two patients with Li–Fraumeni syndrome, to the best of our knowledge, this is the first report suggesting a relationship between the aberrant TP53 variant and PEComa. |
format | Online Article Text |
id | pubmed-8995879 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89958792022-04-12 Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53 Butz, Henriett Lövey, József Szentkereszty, Márton Bozsik, Anikó Tóth, Erika Patócs, Attila Front Oncol Oncology Since the introduction of next-generation sequencing, the frequency of germline pathogenic TP53 variants and the number of cases with unusual clinical presentations have been increasing. This has led to the expansion of the classical Li–Fraumeni syndrome concept to a wider cancer predisposition syndrome designated as the Li–Fraumeni spectrum. Here, we present a case with a malignant, metastatic perivascular epithelioid cell tumor (PEComa) of the thigh muscle and a sinonasal carcinoma harboring a novel TP53 germline splice mutation (NM_000546.5:c.97-2A>C). The classical presentation of LFS in the long-since deceased mother and the presence of a germline TP53 variant in the proband suggested a possible familial TP53-related condition. Complex pathological, molecular, and clinical genetic analyses (whole exome sequencing of germline variants, multigene panel sequencing of tumor DNA, Sanger validation, an in vitro functional test on splicing effect, 3D protein modeling, p53 immunohistochemistry, and pedigree analysis) were performed. The in vitro characterization of the splice mutation supported the pathogenic effect that resulted in exon skipping. A locus-specific loss of heterozygosity in the PEComa but not in the sinonasal carcinoma was identified, suggesting the causative role of the splice mutation in the PEComa pathogenesis, because we excluded known pathogenetic pathways characteristic to PEComas (TSC1/2, TFE3, RAD51B). However, the second hit affecting TP53 in the molecular pathogenesis of the sinonasal carcinoma was not identified. Although PEComa has been reported previously in two patients with Li–Fraumeni syndrome, to the best of our knowledge, this is the first report suggesting a relationship between the aberrant TP53 variant and PEComa. Frontiers Media S.A. 2022-03-28 /pmc/articles/PMC8995879/ /pubmed/35419288 http://dx.doi.org/10.3389/fonc.2022.849004 Text en Copyright © 2022 Butz, Lövey, Szentkereszty, Bozsik, Tóth and Patócs https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Butz, Henriett Lövey, József Szentkereszty, Márton Bozsik, Anikó Tóth, Erika Patócs, Attila Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53 |
title | Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53
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title_full | Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53
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title_fullStr | Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53
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title_full_unstemmed | Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53
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title_short | Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53
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title_sort | case report: a novel pathomechanism in pecoma by the loss of heterozygosity of tp53 |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995879/ https://www.ncbi.nlm.nih.gov/pubmed/35419288 http://dx.doi.org/10.3389/fonc.2022.849004 |
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