Leiomyosarcoma (LMS) is a mesenchymal neoplasm with complex copy-number alterations and characteristic loss of tumor suppressor genes without known recurrent activating mutations. Clinical management of advanced LMS relies on chemotherapy and complementary palliative approaches, and research efforts to date have had limited success identifying clinically actionable biomarkers or targeted therapeutic vulnerabilities. To explore the biological underpinning of LMS, we evaluated gene-expression patterns of this disease in comparison with diverse sarcomas, nonmesenchymal neoplasms, and normal myogenic tissues. We identified a recurrent gene-expression program in LMS, with evidence of oncogenic evolution of an underlying smooth-muscle lineage-derived program characterized by activation of E2F1 and downstream effectors. Recurrently amplified or highly expressed genes in LMS were identified, including IGF1R and genes involved in retinoid signaling pathways. Though the majority of expressed transcripts were conserved across LMS samples, three separate subtypes were identified that were enriched for muscle-associated transcripts (conventional LMS), immune markers (inflammatory LMS), or a uterine-like gene-expression program (uterogenic LMS). Each of these subtypes expresses a unique subset of genes that may be useful in the management of LMS: IGF1R was enriched in conventional LMS, worse disease-specific survival was observed in inflammatory LMS, and prolactin was elaborated by uterogenic LMS. These results extend our understanding of LMS biology and identify several strategies and challenges for further translational investigation. Implications: LMS has a recurrent oncogenic transcriptional program and consists of molecular subtypes with biological and possible clinical implications.

中文翻译：

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平滑肌肉瘤中的致癌基因表达程序以及常规亚型、炎症亚型和子宫亚型的特征


平滑肌肉瘤 (LMS) 是一种间叶性肿瘤，具有复杂的拷贝数改变和肿瘤抑制基因的特征性缺失，且没有已知的复发性激活突变。先进 LMS 的临床管理依赖于化疗和补充姑息治疗方法，迄今为止的研究工作在确定临床上可行的生物标志物或靶向治疗漏洞方面取得的成功有限。为了探索 LMS 的生物学基础，我们与不同的肉瘤、非间质肿瘤和正常肌源性组织进行了比较，评估了该疾病的基因表达模式。我们在 LMS 中发现了一个反复出现的基因表达程序，并有证据表明潜在的平滑肌谱系衍生程序的致癌进化，其特征是 E2F1 和下游效应子的激活。鉴定出 LMS 中反复扩增或高度表达的基因，包括 IGF1R 和参与类维生素A信号通路的基因。尽管大多数表达转录本在 LMS 样本中是保守的，但仍鉴定出三种不同的亚型，这些亚型富含肌肉相关转录本（传统 LMS）、免疫标记物（炎症 LMS）或子宫样基因表达程序（子宫源性 LMS） 。这些亚型中的每一种都表达可能有助于 LMS 管理的独特基因子集：IGF1R 在传统 LMS 中富集，在炎症性 LMS 中观察到较差的疾病特异性生存，而催乳素则由子宫源性 LMS 精心设计。这些结果扩展了我们对 LMS 生物学的理解，并确定了进一步转化研究的几种策略和挑战。 意义：LMS 具有复发性致癌转录程序，由具有生物学和可能的临床意义的分子亚型组成。