Fusion Gene-Negative Alveolar Rhabdomyosarcoma Is Clinically and Molecularly Indistinguishable From Embryonal Rhabdomyosarcoma
Fusion Gene-Negative Alveolar Rhabdomyosarcoma Is Clinically and Molecularly Indistinguishable From Embryonal Rhabdomyosarcoma
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DOI：
10.1200/jco.2009.26.3814
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发表时间：
2010-05-01
影响因子：
45.3
通讯作者：
Delattre, Olivier
中科院分区：
文献类型：
--
作者：
Williamson, Daniel;Missiaglia, Edoardo;Delattre, Olivier
目的探讨肺泡横纹肌肉瘤（ARMS）和胚胎横纹肌肉瘤（ERMS）亚型的临床和分子生物学特征是否与PAX/FOXO1融合基因的存在与否无关。患者与方法采用逆转录聚合酶链反应检测210例经组织病理学检查、临床注释的横纹肌肉瘤标本的融合基因状态。Kaplan-Meier分析用于评估融合基因阴性ARMS （ARMSn, n = 39）、融合基因阳性ARMS （ARMSp, n = 94）和ERMS （n = 77）的无事件生存期和总生存期。共有101个RMS样本进行了全基因组表达分析，128个样本进行了基因组拷贝数失衡分析。通过有监督和无监督的方法对分析数据进行分析，比较与组织病理学和融合基因状态相关的特征。结果也通过跨三个独立的公开数据集的荟萃分析技术进行预测。结果总生存率、无事件生存率、转移频率、首发部位分布在ARMSn和ERMS之间无显著差异。与此一致的是，基因表达特征分析不能重复区分ARMSn和ERMS，而融合基因阳性的病例是不同的。ARMSn和ERMS经常表现出全染色体拷贝数的变化，特别是8号染色体的增加，这条染色体上的基因表达水平较高。结论无融合基因肺泡病例的临床行为和分子特征与胚胎性肺泡病例无明显区别，与融合阳性肺泡病例有显著差异。这意味着融合基因状态与组织学无关，是RMS危险分层的关键因素。
PurposeTo determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene.Patients and MethodsThe fusion gene status of 210 histopathologically reviewed, clinically annotated rhabdomyosarcoma samples was determined by reverse transcriptase polymerase chain reaction. Kaplan-Meier analysis was used to assess event-free survival and overall survival in fusion gene-negative ARMS (ARMSn; n = 39), fusion gene-positive ARMS (ARMSp; n = 94), and ERMS (n = 77). A total of 101 RMS samples were also profiled for whole-genome expression, and 128 were profiled for genomic copy number imbalances. Profiling data were analyzed by supervised and unsupervised methods to compare features related to histopathology and fusion gene status. Results were also projected by meta-analysis techniques across three separate publically available data sets.ResultsOverall and event-free survival, frequency of metastases, and distribution of site at initial presentation were not significantly different between ARMSn and ERMS. Consistent with this, analysis of gene expression signatures could not reproducibly distinguish ARMSn from ERMS whereas fusion gene-positive cases were distinct. ARMSn and ERMS frequently show whole-chromosome copy number changes, notably gain of chromosome 8 with associated high levels of expression of genes from this chromosome.ConclusionThe clinical behavior and molecular characteristics of alveolar cases without a fusion gene are indistinguishable from embryonal cases and significantly different from fusion-positive alveolar cases. This implies that fusion gene status irrespective of histology is a critical factor in risk stratification of RMS.