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: 6232397
• 负责人: FREDERIC G BARR
• 金额: $ 28.93万
• 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/6232397
• 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：腺泡状横纹肌肉瘤是一种侵袭性软组织肉瘤 发生在儿童和年轻人身上的横纹肌肿瘤。 这种癌症与2;13和1;13染色体易位有关， 将PAX 3和PAX 7基因座与FKHR基因座并置以产生嵌合基因 编码PAX 3-FKHR或PAX 7-FKHR融合产物。为了检测这些融合， 肿瘤标本、聚合酶链反应、原位杂交和Southern杂交 已经开发了印迹策略。使用这些分析，Intergroup 横纹肌肉瘤研究小组（IRSG）的初步研究提供了证据表明 这些基因融合是ARMS诊断的特异性标志物， PAX 3-FKHR和PAX&-FKHR亚型与ARMS的不同结局相关 患者，并且高灵敏度测定能够在临床上检测 显著亚显微转移性疾病。此外，最近的研究 提示在ARMS病例中存在其他融合亚型， 可检测地表达典型的PAX 3-FKHR或PAX 7-FKHR融合转录物。的 初步研究支持了融合基因检测将发挥 在ARMS的诊断、监测和管理中发挥重要作用 患者为了进一步探讨这一假设的背景下，一个大的 统一治疗和诊断的多机构临床试验 患者和集中收集的临床标本和临床数据，IRSG 生物学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 前瞻性地进入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ARMS管理中的预测价值。 将研究融合阴性ARMS肿瘤的变异和隐藏基因 融合，以建立额外的融合类别， 临床相关研究。骨髓和外周血标本来自 还将对这些患者进行分析，以确定 转移部位的亚显微疾病检测。最后，生物 将检查增殖和凋亡状态的标志物以确定 它们与这些患者的融合亚型和其他参数的关系。 这些研究将提供一个明确的分析的发生和临床 这些基因改变在ARMS中的重要性，并将最终影响 关于未来设计治疗ARMS患者的临床方案。