Comprehensive mutational profiling identifies new driver events in cutaneous leiomyosarcoma.
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All Authors
van der Weyden, L.
Del Castillo Velasco-Herrera, M.
Cheema, S.
Wong, K.
Boccacino, JM.
Offord, V.
Droop, A.
Jones, DRA.
Vermes, I.
Anderson, E.
LTHT Author
Clarke, Emily
Merchant, William
Merchant, William
LTHT Department
Histopathology
Non Medic
Publication Date
2025
Item Type
Journal Article
Multicenter Study
Multicenter Study
Language
Subject
Subject Headings
Abstract
BACKGROUND: Cutaneous leiomyosarcoma (cLMS) is a rare soft-tissue neoplasm, showing smooth muscle differentiation, that arises from the mesenchymal cells of the dermis. To date, genetic investigation of these tumours has involved studies with small sample sizes and limited analyses that identified recurrent somatic mutations in RB1 and TP53, copy number gain of MYOCD and IGF1R, and copy number loss of PTEN.
OBJECTIVES: To better understand the molecular pathogenesis of cLMS, we comprehensively explored the mutational landscape of these rare tumours to identify candidate driver events.
METHODS: In this retrospective, multi-institutional study, we performed whole-exome sequencing and RNA sequencing in 38 cases of cLMS.
RESULTS: TP53 and RB1 were identified as significantly mutated and thus represent validated driver genes of cLMS. COSMIC mutational signatures SBS7a/b and DBS1 were recurrent; thus, ultraviolet light exposure may be an aetiological factor driving cLMS. Analysis of significantly recurrent somatic copy number alterations, which represent candidate driver events, found focal (< 10 Mb) deletions encompassing TP53 and KDM6B, and amplifications encompassing ZMYM2, MYOCD, MAP2K4 and NCOR1. A larger (24 Mb) recurrent deletion encompassing CYLD was also identified as significant. Significantly recurrent broad copy number alterations, involving at least half of a chromosome arm, included deletions of 6p/q, 10p/q, 11q, 12q, 13q and 16p/q, and amplification of 15q. Notably PTEN is located on 10q, RB1 on 13q and IGFR1 on 15q. Fusion gene analysis identified recurrent CRTC1/CRTC3
Journal
British Journal of Dermatology