Studies of amplification in rhabdomyosarcoma

横纹肌肉瘤扩增的研究

• 批准号: 8349507
• 负责人: Frederic Barr
• 金额: $ 17.03万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349507
• 关键词: 12q13-q14; 13q14; 1p36; Behavior; Biological; Biological Assay; Cell Fraction; Cells; Clinical; Clinical Trials; Correlative Study; Critical Pathways; Event; Fluorescent in Situ Hybridization; Gene Amplification; Genes; Genetic; Goals; Heterogeneity; Laboratories; Malignant Neoplasms; Measures; Molecular; Multivariate Analysis; National Cancer Institute; Oligonucleotide Microarrays; Oncogene Proteins; Other Genetics; Outcome; PAX3 gene; PAX7 gene; Pathogenesis; Pennsylvania; Predictive Value; Research Personnel; Rhabdomyosarcoma; Role; Therapeutic Intervention; Time; Transcript; Universities; base; directed attention; follow-up; fusion gene; improved; novel; outcome forecast; prognostic; research study; tumor

The Senior Investigator moved to the National Cancer Institute during FY2011 and has been setting up the laboratory during the remaining time. Therefore no research studies were performed on this project during FY2011. However, in previous studies at the University of Pennsylvania, the Senior Investigator made the following observations. 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 region 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 rhabdomyosarcoma.

高级研究员于2011财年转移至国家癌症研究所，并在剩余时间内建立实验室。因此，2011财政年度期间未对该项目进行研究。然而，在宾夕法尼亚大学以前的研究中，高级研究员提出了以下观察结果。 基于先前的研究表明融合基因在这些癌症的子集中扩增，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，我们发现最小的1 p36扩增子测量为0.13 Mb，仅包含PAX 7，而最小的13 q14扩增子测量为0.53 Mb区域，包含FOXO 1和表征较差的LOC 646982基因。应用荧光原位杂交分析超过100融合阳性病例显示，融合基因扩增PAX 7-FOXO 1阳性的93%和PAX 3-FOXO 1阳性的9%。虽然扩增的PAX 7-FOXO 1阳性病例中的大多数细胞含有扩增子，但扩增的PAX 3-FOXO 1阳性病例中只有一部分细胞含有扩增子。表达研究表明，在扩增的情况下，融合转录物通常以更高的水平表达，并且PAX 7-FOXO 1融合转录物以比PAX 3-FOXO 1融合转录物更高的水平表达。最后，融合基因扩增和PAX 7-FOXO 1融合状态均与显著改善的结局相关;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横纹肌肉瘤的一个新的预后良好的亚群提供了进一步的证据。