Genomic landscape of endometrial stromal sarcoma of uterus.
Genomic landscape of endometrial stromal sarcoma of uterus.
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DOI：
10.18632/oncotarget.5384
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Lee SH
中科院分区：
文献类型：
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作者：
Choi YJ;Jung SH;Kim MS;Baek IP;Rhee JK;Lee SH;Hur SY;Kim TM;Chung YJ;Lee SH
虽然复发性基因融合，如JAZF 1-JJAZ 1被认为是子宫内膜间质肉瘤（ESS）发展的驱动因素，但其他基因组改变在很大程度上仍然未知。在这项研究中，我们进行了全外显子组测序，转录组测序和拷贝数分析五个ESS（三个低级别ESS（LG-ESS）和两个未分化子宫肉瘤（UUS））。所有三种LG-ESS均表现出JAZF 1-SUZ 12、JAZF 1-PHF 1和MEAF 6-PHF 1融合中的任一种，而两种UUS则没有。除了一个LG-ESS外，所有ESS都表现出拷贝数改变（CNA），其中许多包含癌症相关基因。在UUS中，包含癌相关基因EZR、CDH 1、RB 1、TP 53和PRKAR 1A的5个CNA伴随着它们的表达变化，提示它们可能刺激UUS的发展。我们发现了81个非沉默突变（35个来自LG-ESS，46个来自UUS），其中包括15个在癌症相关数据库中编目的推定癌症基因，包括PPARG和IRF 4突变。然而，它们是非复发性的，不包括任何已知的突变，表明点突变可能不是ESS发展的主要驱动因素。我们的数据表明，基因融合和CNA分别是LG-ESS和USS的主要驱动因素，但两者都可能需要额外的基因组改变，包括点突变。这些差异可能解释了LG-ESS与UUS生物学行为的差异。我们的研究结果表明，ESS的发展需要点突变和CNA以及基因融合。
Although recurrent gene fusions such as JAZF1-JJAZ1 are considered driver events for endometrial stromal sarcoma (ESS) development, other genomic alterations remain largely unknown. In this study, we performed whole-exome sequencing, transcriptome sequencing and copy number profiling for five ESSs (three low-grade ESS (LG-ESS) and two undifferentiated uterine sarcomas (UUSs)). All three LG-ESSs exhibited either one of JAZF1-SUZ12, JAZF1-PHF1 and MEAF6-PHF1 fusions, whereas the two UUSs did not. All ESSs except one LG-ESS exhibited copy number alterations (CNAs), many of which encompassed cancer-related genes. In UUSs, five CNAs encompassing cancer-related genes (EZR, CDH1, RB1, TP53 and PRKAR1A) accompanied their expressional changes, suggesting that they might stimulate UUS development. We found 81 non-silent mutations (35 from LG-ESSs and 46 from UUSs) that included 15 putative cancer genes catalogued in cancer-related databases, including PPARG and IRF4 mutations. However, they were non-recurrent and did not include any well-known mutations, indicating that point mutations may not be a major driver for ESS development. Our data show that gene fusions and CNAs are the principal drivers for LG-ESS and USS, respectively, but both may require additional genomic alterations including point mutations. These differences may explain the different biologic behaviors between LG-ESS and UUS. Our findings suggest that ESS development requires point mutations and CNAs as well as the gene fusions.