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Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies

Malignant sweat gland tumours are rare, with the most common form being Eccrine porocarcinoma (EP). To investigate the mutational landscape of EP, we performed whole-exome sequencing (WES) on 14 formalin-fixed paraffin-embedded samples of matched primary EP and healthy surrounding tissue. Mutational...

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Autores principales: Denisova, Evgeniya, Westphal, Dana, Surowy, Harald M., Meier, Friedegund, Hutter, Barbara, Reifenberger, Julia, Rütten, Arno, Schulz, Alexander, Sergon, Mildred, Ziemer, Mirjana, Brors, Benedikt, Betz, Regina C., Redler, Silke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9209330/
https://www.ncbi.nlm.nih.gov/pubmed/34045664
http://dx.doi.org/10.1038/s41417-021-00347-z
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author Denisova, Evgeniya
Westphal, Dana
Surowy, Harald M.
Meier, Friedegund
Hutter, Barbara
Reifenberger, Julia
Rütten, Arno
Schulz, Alexander
Sergon, Mildred
Ziemer, Mirjana
Brors, Benedikt
Betz, Regina C.
Redler, Silke
author_facet Denisova, Evgeniya
Westphal, Dana
Surowy, Harald M.
Meier, Friedegund
Hutter, Barbara
Reifenberger, Julia
Rütten, Arno
Schulz, Alexander
Sergon, Mildred
Ziemer, Mirjana
Brors, Benedikt
Betz, Regina C.
Redler, Silke
author_sort Denisova, Evgeniya
collection PubMed
description Malignant sweat gland tumours are rare, with the most common form being Eccrine porocarcinoma (EP). To investigate the mutational landscape of EP, we performed whole-exome sequencing (WES) on 14 formalin-fixed paraffin-embedded samples of matched primary EP and healthy surrounding tissue. Mutational profiling revealed a high overall median mutation rate. This was attributed to signatures of mutational processes related to ultraviolet (UV) exposure, APOBEC enzyme dysregulation, and defective homologous double-strand break repair. All of these processes cause genomic instability and are implicated in carcinogenesis. Recurrent driving somatic alterations were detected in the EP candidate drivers TP53, FAT2, CACNA1S, and KMT2D. The analyses also identified copy number alterations and recurrent gains and losses in several chromosomal regions including that containing BRCA2, as well as deleterious alterations in multiple HRR components. In accordance with this reduced or even a complete loss of BRCA2 protein expression was detected in 50% of the investigated EP tumours. Our results implicate crucial oncogenic driver pathways and suggest that defective homologous double-strand break repair and the p53 pathway are involved in EP aetiology. Targeting of the p53 axis and PARP inhibition, and/or immunotherapy may represent promising treatment strategies.
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spelling pubmed-92093302022-06-22 Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies Denisova, Evgeniya Westphal, Dana Surowy, Harald M. Meier, Friedegund Hutter, Barbara Reifenberger, Julia Rütten, Arno Schulz, Alexander Sergon, Mildred Ziemer, Mirjana Brors, Benedikt Betz, Regina C. Redler, Silke Cancer Gene Ther Article Malignant sweat gland tumours are rare, with the most common form being Eccrine porocarcinoma (EP). To investigate the mutational landscape of EP, we performed whole-exome sequencing (WES) on 14 formalin-fixed paraffin-embedded samples of matched primary EP and healthy surrounding tissue. Mutational profiling revealed a high overall median mutation rate. This was attributed to signatures of mutational processes related to ultraviolet (UV) exposure, APOBEC enzyme dysregulation, and defective homologous double-strand break repair. All of these processes cause genomic instability and are implicated in carcinogenesis. Recurrent driving somatic alterations were detected in the EP candidate drivers TP53, FAT2, CACNA1S, and KMT2D. The analyses also identified copy number alterations and recurrent gains and losses in several chromosomal regions including that containing BRCA2, as well as deleterious alterations in multiple HRR components. In accordance with this reduced or even a complete loss of BRCA2 protein expression was detected in 50% of the investigated EP tumours. Our results implicate crucial oncogenic driver pathways and suggest that defective homologous double-strand break repair and the p53 pathway are involved in EP aetiology. Targeting of the p53 axis and PARP inhibition, and/or immunotherapy may represent promising treatment strategies. Nature Publishing Group US 2021-05-27 2022 /pmc/articles/PMC9209330/ /pubmed/34045664 http://dx.doi.org/10.1038/s41417-021-00347-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Denisova, Evgeniya
Westphal, Dana
Surowy, Harald M.
Meier, Friedegund
Hutter, Barbara
Reifenberger, Julia
Rütten, Arno
Schulz, Alexander
Sergon, Mildred
Ziemer, Mirjana
Brors, Benedikt
Betz, Regina C.
Redler, Silke
Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies
title Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies
title_full Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies
title_fullStr Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies
title_full_unstemmed Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies
title_short Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies
title_sort whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9209330/
https://www.ncbi.nlm.nih.gov/pubmed/34045664
http://dx.doi.org/10.1038/s41417-021-00347-z
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