Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

Abstract

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)697-708
Seitenumfang12
FachzeitschriftCancer Gene Therapy
Jahrgang29
Ausgabenummer6
PublikationsstatusVeröffentlicht - Juni 2022
Peer-Review-StatusJa

Externe IDs

PubMed 34045664
ORCID /0000-0001-7499-5125/work/142253612
ORCID /0000-0003-4340-9706/work/143497451
ORCID /0000-0003-4340-0402/work/145223794

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