New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics
New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics
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DOI：
10.1002/path.2787
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发表时间：
2011-01-01
影响因子：
7.3
通讯作者：
Aurias, Alain
中科院分区：
文献类型：
--
作者：
Gibault, Laure;Perot, Gaelle;Aurias, Alain
成人软组织肉瘤是一种罕见的间叶性肿瘤。根据细胞遗传学和比较基因组杂交（CGH）数据，它们可以分为“具有简单基因组的STS”，显示特征性的遗传改变，和“具有复杂基因组的STS”（SCG），其中发生多个基因组改变。后一组主要由平滑肌肉瘤（LMS）和以前标记为“恶性纤维组织细胞瘤”（MFH）的多形性未分化肿瘤组成，实际上对应于粘液纤维肉瘤（MFS），多形性脂肪肉瘤/横纹肌肉瘤（P-LPS，P-RMS）和未分化多形性肉瘤（UPS）。其病理生物学仍然没有得到很好的理解，导致诊断和治疗管理的挑战。我们在这里报告一个全面的研究，包括阵列CGH和转录组分析数据的一个大系列的160 SCG。转录组数据的非监督聚类导致五组肿瘤的鉴定，其中一组（A组）对应于分化良好的LMS，另外四组（B-E）对应于“MFH”和分化不良的LMS。Welch分析这些组中的转录组数据使我们能够检索到几个潜在的感兴趣的基因。其中，RB 1的改变是SCG中的一个恒定线索，通常与RBL 2丢失相关。PTEN肿瘤抑制基因缺失也是一个主要的复发事件，特别是在A、C和D组中。可能涉及WNT经典途径，如其抑制剂之一DKK 1在D组和E组中上调所示，而DKK 1在A、B和C组中显著下调。这些数据表明，PTEN下游途径和WNT经典途径之间存在非常复杂的相互作用，为SCG病理生物学及其潜在治疗靶点提供了新的提示。版权所有（C）2010大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Adult soft tissue sarcomas (STS) are rare tumours of mesenchymal lineage. Based on cytogenetic and comparative genomic hybridization (CGH) data, they can be divided into 'STS with simple genomics', displaying a characteristic genetic alteration, and 'STS with complex genomics' (SCG), where multiple genomic alterations occur. This latter group is mostly composed of leiomyosarcomas (LMS) and pleiomorphic undifferentiated tumours previously labelled as 'malignant fibrous histiocytomas' (MFH), corresponding in fact to myxofibrosarcomas (MFS), pleiomorphic liposarcomas/rhabdomyosarcomas (P-LPS, P-RMS), and undifferentiated pleiomorphic sarcomas (UPS). Their pathobiology is still not well understood, leading to challenges in diagnosis and therapeutic management. We report here a comprehensive study encompassing array-CGH and transcriptome analysis data of a large series of 160 SCG. Non-supervised clustering of transcriptome data led to the identification of five groups of tumours, one of them (group A) corresponding to well-differentiated LMS and the other four (B-E) to 'MFH' and poorly differentiated LMS. Welch analysis of transcriptome data in these groups allowed us to retrieve several genes of potential interest. Among them, RB1 alteration is a constant thread in SCG, often associated with RBL2 loss. PTEN tumour suppressor deletion would also stand out as a major recurrent event, especially in groups A, C, and D. The WNT canonical pathway could be potentially involved, as demonstrated by up-regulation of one of its inhibitors, DKK1, in groups D and E, whereas DKK1 is significantly down-regulated in groups A, B, and C. These data suggest a very complex interplay between pathways downstream of PTEN and the WNT canonical pathway, providing new hints about SCG pathobiology and their potential therapeutic targets. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.