Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies.

Autor: Denisova E; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany., Westphal D; Department of Dermatology, Carl Gustav Carus Medical Center, TU Dresden, Dresden, Germany.; National Centre for Tumour Diseases (NCT), Partner Site Dresden, Dresden, Germany., Surowy HM; Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Meier F; Department of Dermatology, Carl Gustav Carus Medical Center, TU Dresden, Dresden, Germany.; National Centre for Tumour Diseases (NCT), Partner Site Dresden, Dresden, Germany., Hutter B; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), Heidelberg, Germany., Reifenberger J; Department of Dermatology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Rütten A; Dermatopathology, Bodensee, Siemensstrasse 6/1, 88048, Friedrichshafen, Germany., Schulz A; National Centre for Tumour Diseases (NCT), Partner Site Dresden, Dresden, Germany., Sergon M; Institute of Pathology, Carl Gustav Carus Medical Center, TU Dresden, Dresden, Germany., Ziemer M; Department of Dermatology, Venereology and Allergology, University Medical Center, Leipzig, Germany., Brors B; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; National Center for Tumor Diseases (NCT), Heidelberg, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Betz RC; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Redler S; Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. silke.redler@med.uni-duesseldorf.de.
Jazyk: angličtina
Zdroj: Cancer gene therapy [Cancer Gene Ther] 2022 Jun; Vol. 29 (6), pp. 697-708. Date of Electronic Publication: 2021 May 27.
DOI: 10.1038/s41417-021-00347-z
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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