Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: A report from the Children's Oncology Group
Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: A report from the Children's Oncology Group
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DOI：
10.1002/gcc.21953
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发表时间：
2012-07-01
影响因子：
3.7
通讯作者：
Barr, Frederic G.
中科院分区：
文献类型：
--
作者：
Duan, Fenghai;Smith, Lynette M.;Barr, Frederic G.
腺泡状横纹肌肉瘤 (RMS) 是一种侵袭性儿童肌源性癌症，具有频繁的涉及 PAX3 或 PAX7 和 FOXO1 基因的染色体易位。基于先前的研究表明融合基因在这些癌症的子集中被扩增，我们对这些扩增事件进行了全面的分子和临床研究。使用寡核苷酸阵列定位扩增子，我们发现最小 1p36 扩增子测量为 0.13 Mb，仅包含 PAX7，而最小 13q14 扩增子测量为 0.53 Mb，包含 FOXO1 和特征较差的 LOC646982 基因。对 100 多个融合阳性病例应用荧光原位杂交测定表明，融合基因在 93% 的 PAX7-FOXO1 阳性病例和 9% 的 PAX3-FOXO1 阳性病例中扩增。虽然扩增的 PAX7-FOXO1 阳性病例中的大多数细胞含有扩增子，但扩增的 PAX3-FOXO1 阳性病例中只有一小部分细胞含有扩增子。表达研究表明，在扩增病例中，融合转录本通常以较高水平表达，并且PAX7-FOXO1融合转录本的表达水平高于PAX3-FOXO1融合转录本。最后，融合基因扩增和 PAX7-FOXO1 融合状态均与显着改善的结果相关；多变量分析表明，该预测值独立于其他标准预后参数。因此，这些发现为融合阳性 RMS 的新的良好预后子集提供了进一步的证据。 (c) 2012 年 Wiley 期刊公司。
Alveolar rhabdomyosarcoma (RMS) is an aggressive pediatric cancer of the myogenic lineage with frequent chromosomal translocations involving the PAX3 or PAX7 and FOXO1 genes. Based on previous studies indicating that the fusion genes are amplified in a subset of these cancers, we conducted a comprehensive molecular and clinical investigation of these amplification events. Using oligonucleotide arrays to localize amplicons, we found that the minimal 1p36 amplicon measured 0.13 Mb and only contained PAX7 whereas the minimal 13q14 amplicon measured 0.53 Mb and contained FOXO1 and the poorly characterized LOC646982 gene. Application of a fluorescence in situ hybridization assay to over 100 fusion-positive cases revealed that the fusion gene is amplified in 93% of PAX7-FOXO1-positive and 9% of PAX3-FOXO1-positive cases. While most cells in amplified PAX7-FOXO1-positive cases contained the amplicon, only a fraction of cells in the amplified PAX3-FOXO1-positive cases contained the amplicon. Expression studies demonstrated that the fusion transcripts were generally expressed at higher levels in amplified cases, and that the PAX7-FOXO1 fusion transcript was expressed at higher levels than the PAX3-FOXO1 fusion transcript. Finally, fusion gene amplification and PAX7-FOXO1 fusion status were each associated with significantly improved outcome; a multivariate analysis demonstrated that this predictive value was independent of other standard prognostic parameters. These findings therefore provide further evidence for a novel good prognosis subset of fusion-positive RMS. (c) 2012 Wiley Periodicals, Inc.