Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group.
Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group.
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DOI：
10.1158/1078-0432.ccr-10-0091
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发表时间：
2011-03-15
期刊：
影响因子：
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通讯作者：
Barr FG
中科院分区：
文献类型：
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作者：
Reichek JL;Duan F;Smith LM;Gustafson DM;O'Connor RS;Zhang C;Dunlevy MJ;Gastier-Foster JM;Barr FG
本研究确定了肺泡横纹肌肉瘤 (ARMS) 中 13q31 染色体区域扩增的分子特征和临床意义，ARMS 是一种具有频繁 PAX3-FOXO1 和 PAX7-FOXO1 基因融合的侵袭性儿科癌症。使用寡核苷酸阵列将 13q31 扩增子定位于 ARMS 病例的初始组中。设计了针对该局部区域的荧光原位杂交测定，并将其应用于更多的 ARMS 病例，以确定扩增的频率和分布。应用定量逆转录-PCR 测定来测量基因表达。使用 Kaplan-Meier 和 Cox 比例风险模型确定拷贝数和表达的临床意义。我们将 13q31 扩增子定位到包含编码多顺反子 microRNA 簇 miR-17-92 的 MIR17HG 基因的 0.15 Mb 区域。该扩增子存在于 23% 的 ARMS 病例中，并且明显偏爱 PAX7-FOXO1 阳性病例。在 13q31 扩增的肿瘤中，miR-17-92 簇内 6 个 microRNA 中的 5 个（miR-17、miR-19a、miR-19b、miR-20a 和 miR-92）的表达显着增加。此外，还鉴定出了所有六种 microRNA 均具有拷贝数独立过度表达的非扩增肿瘤子集。在临床分析中，与非扩增病例相比，13q31 扩增病例中上述 5 种 microRNA 表达增加的结果明显更差。在这些 microRNA 表达较低的 13q31 扩增病例中，结果也有所改善。 miR-17-92 簇的 13q31 扩增和表达为识别 PAX7-FOXO1 阳性 ARMS 的良好和不良预后子集提供了新的标记。
This study determined the molecular characteristics and clinical significance of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma (ARMS), an aggressive pediatric cancer with frequent PAX3-FOXO1 and PAX7-FOXO1 gene fusions. The 13q31 amplicon was localized in an initial panel of ARMS cases using oligonucleotide arrays. A fluorescence in situ hybridization assay for this localized region was designed, and applied to more ARMS cases to determine the frequency and distribution of amplification. Quantitative reverse transcription-PCR assays were applied to measure gene expression. The clinical significance of copy number and expression was determined with Kaplan-Meier and Cox proportional hazard models. We localized the 13q31 amplicon to a 0.15 Mb region containing the MIR17HG gene encoding the polycistronic microRNA cluster, miR-17-92. This amplicon is present in 23% of ARMS cases with a marked preference for PAX7-FOXO1-positive cases. In tumors with 13q31 amplification, there is significantly increased expression of five of six microRNA’s within the miR-17-92 cluster (miR-17, miR-19a, miR-19b, miR-20a, and miR-92). In addition, a subset of non-amplified tumors with copy number-independent overexpression of all six microRNA’s was identified. In clinical analyses, there was a significantly worse outcome associated with increased expression of the five microRNA’s described above in 13q31-amplified cases when compared to non-amplified cases. There was also an improved outcome in 13q31-amplified cases with lower expression of these microRNA’s. 13q31 amplification and expression of the miR-17-92 cluster provide novel markers for identifying good and poor prognostic subsets of PAX7-FOXO1-positive ARMS.