IRSG LABORATORY CORRELATIVE STUDIES

儿童横纹肌肉瘤(RMS)的组织病理学分类 已建立的亚型与不同的临床相关联 特点。亚型之间的区别得到了加强 通过分子研究证实PAX3/PAX7-FKHR基因融合在 胚胎肺泡RMS与染色体11p15.5等位基因缺失 均方根。尽管这种分类系统很有用，但临床上 在这些亚型中存在异质性，例如站点， 阶段和结果。作为这种异质性的潜在关联， 其他原癌基因和肿瘤抑制基因的变化 在较小的RMS肿瘤亚群中检测到。特别是，基因突变 P53和RAS基因、MYCN和12q13-15基因座的扩增 据报道，在RMS病例中CDKN2A基因缺失。其中一些 更改优先发生在单个子类型中，而其他子类型 在所有亚型中，改变发生的频率都很低。这些发现 表明RMS的发病机制可以描述为多步骤的 涉及协作的基本子类型特定事件的流程 与其他子类型特定和非特定事件一起使用。事件的发生 仅在每个RMS子类型的子集中进行更改就提供了 这些类别中的遗传异质性可能提供 对临床异质性的解释。在此应用程序中， 跨组横纹肌肉瘤研究(IRS)组生物学委员会 将研究P53和RAS家族突变的临床意义， MYCN和12q13-15扩增，以及CDKN2A在大面板中的改变 特征明确的RMS肿瘤从密切监测的 并统一治疗国税局试验的患者。特别是，我们 将检测这些基因的每一个变化以及PAX3/PAX7- 从IRS-IV到IRS-IV的一组98例冷冻肿瘤标本中FKHR的融合状态 建立总的频率和与病理和 这些病例的临床特点。基于这些发现， 将通过对特定关联的定向分析来进一步检查 来自中国的精选肿瘤标本中的特定基因改变 收藏了900多块IRS-III石蜡块。这些研究将 提供对发生情况和临床情况的明确分析 这些基因改变在RMS中的意义，并识别新的 这些标记物将在未来的IRS研究中进一步分析。

Histopathologic classification of pediatric rhabdomyosarcoma (RMS) has established subtypes that are associated with distinct clinical characteristics. The distinction between the subtypes is strengthened by molecular studies that identified PAX3/PAX7-FKHR gene fusions in alveolar RMS and allelic loss of chromosomal region 11p15.5 in embryonal RMS. Despite the utility of this classification system, clinical heterogeneity exists within these subtypes in such parameters as site, stage, and outcome. As a potential correlate of this heterogeneity, alterations of other prot-oncogenes and tumor suppressor genes have been detected in smaller subsets of RMS tumors. In particular, mutations of p53 and RAS genes, amplification of MYCN and 12q13-15 loci, and deletions of CDKN2A have been reported in cases of RMS. Some of these changes occur preferentially in a single subtype whereas other alterations occur at a low frequency in all subtypes. These findings indicate that RMS pathogenesis can be characterized as a multistep process involving fundamental subtype-specific events that collaborate with other subtype-specific and non-specific events. The occurrence of alterations in only a subset of each RMS subtype provides the basis for genetic heterogeneity within these categories that may provide an explanation for clinical heterogeneity. In this application, the Biology Committee of the Intergroup Rhabdomyosarcoma Study (IRS) Group will examine the clinical significance of p53 and RAS family mutations, MYCN and 12q13-15 amplification, and CDKN2A alterations in a large panel of well-characterized RMS tumors collected from the closely monitored and uniformly treated patients of the IRS trials. In particular, we will assay for each of these genetic alterations as well as PAX3/PAX7- FKHR fusion status in a set of 98 frozen tumor samples from IRS-IV to establish the overall frequencies and associations with pathologic and clinical characteristics of these cases. Based on these findings, specific associations will be further examined by directed analysis of specific genetic alterations in selected tumor specimens from the collection of over 900 paraffin blocks of IRS-III. These studies will provide a definitive analysis of the occurrence and clinical significance of these genetic alterations in RMS, and identify novel markers that will be analyzed further in prospective IRS studies.