Clinically Relevant Molecular Subtypes in Leiomyosarcoma.
Clinically Relevant Molecular Subtypes in Leiomyosarcoma.
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DOI：
10.1158/1078-0432.ccr-14-3141
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发表时间：
2015-08-01
期刊：
影响因子：
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通讯作者：
van de Rijn M
中科院分区：
文献类型：
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作者：
Guo X;Jo VY;Mills AM;Zhu SX;Lee CH;Espinosa I;Nucci MR;Varma S;Forgó E;Hastie T;Anderson S;Ganjoo K;Beck AH;West RB;Fletcher CD;van de Rijn M
平滑肌肉瘤（LMS）是一种具有平滑肌分化的恶性肿瘤。关于它的分子异质性知之甚少，目前还没有针对LMS的靶向治疗。识别不同的分子亚型是必要的，以评估新的治疗方案。在之前对51个LMS的研究中，我们确定了LMS中的三种分子亚型。本研究旨在确定是否可以在独立队列中证实这些亚型的存在。应用3′端RNA测序技术（3SEQ）对99例LMS进行基因表达谱分析。进行一致性聚类以确定亚型的最佳数量。我们鉴定了3种LMS分子亚型，并通过分析来自癌症基因组图谱（TCGA）的82种LMS的临床可用数据证实了这一发现。我们确定了两个新的FFPE组织相容性诊断免疫组织化学标记物; LMOD 1亚型I LMS和ARL 4C亚型II LMS。具有已知临床结果的LMS组织微阵列用于显示亚型I LMS与子宫外LMS的良好结果相关，而亚型II LMS与子宫和子宫外LMS的不良预后相关。LMS亚型显示出正在开发的新型靶向治疗的基因表达水平的显着差异，表明LMS亚型可能对这些靶向治疗有差异反应。我们使用两个独立的数据集证实LMS中存在3种分子亚型，并表明不同的分子亚型与不同的临床结局相关。这些发现为以亚型特异性靶向方法治疗LMS提供了机会。
Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 LMS, we identified three molecular subtypes in LMS. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts. 99 cases of LMS were expression profiled with 3′end RNA-Sequencing (3SEQ). Consensus Clustering was conducted to determine the optimal number of subtypes. We identified 3 LMS molecular subtypes and confirmed this finding by analyzing publically available data on 82 LMS from The Cancer Genome Atlas (TCGA). We identified two new FFPE tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I LMS and ARL4C for subtype II LMS. An LMS tissue microarray with known clinical outcome was used to show that subtype I LMS is associated with good outcome in extrauterine LMS while subtype II LMS is associated with poor prognosis in both uterine and extrauterine LMS. The LMS subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that LMS subtypes may respond differentially to these targeted therapies. We confirm the existence of 3 molecular subtypes in LMS using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating LMS in a subtype-specific targeted approach.