Comprehensive mutational profiling identifies new driver events in cutaneous leiomyosarcoma

作者：Louise van der Weyden, Martin Del Castillo Velasco‐Herrera, Saamin Cheema, Kim Ping Wong, Jacqueline Marcia Boccacino, Victoria Offord, Alastair Droop, David R A Jones, Ian Vermes, Elizabeth Anderson, Claire Hardy, Nicolas de Saint Aubain, Peter M. Ferguson, Emily L. Clarke, William Merchant, Carolin Mogler, Derek Frew, Paul W. Harms, Carlos Monteagudo, Steven D. Billings, Mark J. Arends, Ingrid Ferreira, Thomas Brenn, David J. Adams · 发表于：British Journal of Dermatology · 年份：2024 · DOI：10.1093/bjd/ljae386 · 被引用次数：9 · 研究领域：Sarcoma Diagnosis and Treatment、Soft tissue tumors and treatment、Vascular Tumors and Angiosarcomas

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 P...