Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA.
Nat Genet. 2010 Aug;42(8):715-21. doi: 10.1038/ng.619. Epub 2010 Jul 4.
Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
软组织肉瘤在美国每年导致约 10700 例诊断和 3800 例死亡，表现出显著的组织学多样性，有超过 50 种公认的亚型。然而，它们的基因组改变的知识是有限的。我们描述了对涵盖七个主要亚型的 207 个样本的 DNA 序列、拷贝数和 mRNA 表达的综合分析。经常发生突变的基因包括 TP53（多形性脂肪肉瘤的 17%）、NF1（黏液纤维肉瘤的 10.5%和多形性脂肪肉瘤的 8%）和 PIK3CA（黏液性/圆形细胞脂肪肉瘤或 MRC 的 18%）。MRC 中的 PIK3CA 突变与 Akt 激活和不良临床结局相关。在黏液纤维肉瘤和多形性脂肪肉瘤中，我们发现了影响肿瘤抑制基因 NF1 的点突变和基因组缺失。最后，我们发现，针对去分化脂肪肉瘤中扩增的几个基因（包括 CDK4 和 YEATS4）的短发夹 RNA（shRNA）敲低降低了细胞增殖。我们的研究提供了不同肉瘤亚型中分子改变的详细图谱，并提示了潜在的治疗方法。
