全面的突变分析确定了皮肤平滑肌肉瘤中的新驱动事件。
Comprehensive mutational profiling identifies new driver events in cutaneous leiomyosarcoma.
作者信息
van der Weyden Louise, Del Castillo Velasco-Herrera Martin, Cheema Saamin, Wong Kim, Boccacino Jacqueline M, Offord Victoria, Droop Alastair, Jones David R A, Vermes Ian, Anderson Elizabeth, Hardy Claire, de Saint Aubain Nicolas, Ferguson Peter M, Clarke Emily L, Merchant William, Mogler Carolin, Frew Derek, Harms Paul W, Monteagudo Carlos, Billings Steven D, Arends Mark J, Ferreira Ingrid, Brenn Thomas, Adams David J
机构信息
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
出版信息
Br J Dermatol. 2025 Jan 24;192(2):335-343. doi: 10.1093/bjd/ljae386.
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::MAML2 fusions, as well as many novel fusions in individual samples.
CONCLUSIONS
Our analysis of the largest number of cases of cLMS to date highlights the importance of large cohort sizes and exploration beyond small targeted gene panels when performing molecular analyses, as it allowed a comprehensive exploration of the mutational landscape of these tumours and identification of novel candidate driver events. It also uniquely afforded the opportunity to compare the molecular phenotype of cLMS with LMS of other tissue types, such as uterine and soft-tissue LMS. Given that molecular profiling has resulted in the development of novel targeted treatment approaches for uterine and soft-tissue LMS, our study now allows the same opportunities to become available for patients with cLMS.
背景
皮肤平滑肌肉瘤（cLMS）是一种罕见的软组织肿瘤，具有平滑肌分化特征，起源于真皮间充质细胞。迄今为止，对这些肿瘤的基因研究样本量较小且分析有限，已确定RB1和TP53存在复发性体细胞突变、MYOCD和IGF1R拷贝数增加以及PTEN拷贝数缺失。
目的
为了更好地理解cLMS的分子发病机制，我们全面探索了这些罕见肿瘤的突变图谱，以确定候选驱动事件。
方法
在这项回顾性、多机构研究中，我们对38例cLMS进行了全外显子测序和RNA测序。
结果
TP53和RB1被确定为有显著突变，因此是cLMS的验证驱动基因。COSMIC突变特征SBS7a/b和DBS1反复出现；因此，紫外线暴露可能是驱动cLMS的一个病因。对代表候选驱动事件的显著复发性体细胞拷贝数改变的分析发现，包含TP53和KDM6B的局灶性（<10 Mb）缺失，以及包含ZMYM2、MYOCD、MAP2K4和NCOR1的扩增。还发现一个更大的（24 Mb）包含CYLD的复发性缺失具有显著性。涉及至少一半染色体臂的显著复发性广泛拷贝数改变包括6p/q、10p/q、11q、12q、13q和16p/q的缺失，以及15q的扩增。值得注意的是，PTEN位于10q，RB1位于13q，IGFR1位于15q。融合基因分析确定了复发性CRTC1/CRTC3::MAML2融合，以及个别样本中的许多新融合。
结论
我们对迄今为止最大数量的cLMS病例的分析强调了在进行分子分析时大样本量和超越小靶向基因panel进行探索的重要性，因为这使得能够全面探索这些肿瘤的突变图谱并识别新的候选驱动事件。它还独特地提供了将cLMS的分子表型与其他组织类型的平滑肌肉瘤（如子宫和软组织平滑肌肉瘤）进行比较的机会。鉴于分子谱分析已促成子宫和软组织平滑肌肉瘤新靶向治疗方法的开发，我们的研究现在为cLMS患者提供了同样的机会。
Zotero 插件