IRSG STUDIES OF ALVEOLAR RHABDOMYOSARCOMA GENE FUSIONS

肺泡横纹肌肉瘤基因融合的 IRSG 研究

• 批准号: 6701283
• 负责人: FREDERIC G BARR
• 金额: $ 24.06万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-14 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701283
• 关键词: DNA damage; DNA topoisomerases; apoptosis; cell proliferation; chromosome translocation; clinical research; enzyme activity; fluorescent in situ hybridization; gene rearrangement; human subject; immunocytochemistry; metastasis; neoplasm /cancer genetics; polymerase chain reaction; rhabdomyosarcoma; southern blotting; transcription factor

DESCRIPTION: Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue tumor of the striated muscle lineage that occurs in children and young adults. This cancer is associated with 2;13 and 1;13 chromosomal translocations that juxtapose the PAX3 and PAX7 loci with the FKHR locus to create chimeric genes encoding PAX3-FKHR or PAX7-FKHR fusion products. To detect these fusions in tumor specimens, polymerase chain reaction, in situ hybridization, and Southern blot strategies have been developed. Using these assays, Intergroup Rhabdomyosarcoma Study Group (IRSG) pilot studies provided evidence to indicate that these gene fusions are specific markers for ARMS diagnosis, that the PAX3-FKHR and PAX&-FKHR subtypes are associated with differing outcomes in ARMS patients, and that high sensitivity assays are capable of detecting clinically significant submicroscopic metastatic disease. In addition, recent studies suggest the existence of additional fusion subtypes in ARMS cases that do not detectably express the typical PAX3-FKHR or PAX7-FKHR fusion transcripts. The preliminary studies support the hypotheses that fusion gene detection will play a significant role in the diagnosis, monitoring, and management of ARMS patients. To further explore this hypothesis in the setting of a large multi-institutional clinical trial with uniformly treated and diagnosed patients and centrally collected clinical specimens and clinical data, the IRSG Biology Committee will study the relationship of fusion subtype to clinical outcome, other patient characteristics, histopathologic features, and other biological parameters in the patients prospectively entered on the IRS-V study. Gene fusion subtype of the primary tumor will be compared with clinical data to determine the predictive value of these genetic markers in ARMS management. Fusion negative ARMS tumors will be investigated for variant and cryptic gene fusions to establish additional fusion categories for consideration in these clinical correlative studies. Bone marrow and peripheral blood specimens from these patients will also be assayed to determine the predictive value of submicroscopic disease detection in metastatic sites. Finally, biological markers of proliferation and apoptosis status will be examined to determine their relationship with fusion subtype and other parameters in these patients. These studies will provide a definitive analysis of the occurrence and clinical significance of these genetic alterations in ARMS, and will ultimately impact on the future design of clinical protocols for the treatment of ARMS patients.

描述：肺泡型横纹肌肉瘤(ARM)是一种侵袭性软组织 见于儿童和年轻人的横纹肌谱系的肿瘤。 这种癌症与2；13和1；13染色体易位有关， 将PAX3和PAX7基因座与FKHR基因座并列以创建嵌合基因 编码PAX3-FKHR或PAX7-FKHR融合产物。为了检测这些融合 肿瘤标本、聚合酶链式反应、原位杂交和Southern 杂交策略已经被开发出来。使用这些分析，集团间 横纹肌肉瘤研究小组(IRSG)的试点研究提供了证据表明 这些基因融合是武器诊断的特异性标志， Pax3-FKHR和PAX-FKHR亚型与ARM的不同结局相关 患者，而且高灵敏度的检测能够在临床上检测到 重要的亚显微转移疾病。此外，最近的研究 提示在武器病例中存在额外的融合亚型 检测到典型的PAX3-FKHR或PAX7-FKHR融合转录本的表达。这个 初步研究支持融合基因检测将发挥作用的假设 在武器的诊断、监测和管理方面发挥重要作用 病人。为了进一步探讨这一假设，在一个大型的 统一治疗、统一诊断的多机构临床试验 患者和中心收集的临床标本和临床数据，IRSG 生物委员会将研究融合亚型与临床的关系 结果、其他患者特征、组织病理学特征和其他 预期进入IRS-V研究的患者的生物学参数。 原发肿瘤的基因融合亚型将与临床数据进行比较 确定这些遗传标记在军备管理中的预测价值。 融合阴性手臂肿瘤将研究变异和隐蔽基因 融合以建立更多的融合类别以供在这些 临床相关研究。患者的骨髓和外周血样本 还将对这些患者进行检测，以确定其预测价值 转移部位的亚显微疾病检测。最后，生物学上的 将检测增殖和凋亡状态的标志物，以确定 它们与患者融合亚型及其他参数的关系。 这些研究将提供对发生和临床的明确分析。 这些基因改变在手臂上的意义，并最终将影响 关于未来治疗ARM患者的临床方案的设计。