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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group US
2021
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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. |
format | Online Article Text |
id | pubmed-9209330 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
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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