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: 6628497
• 负责人: FREDERIC G BARR
• 金额: $ 24.34万
• 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/6628497
• 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：肺泡横纹肌肉瘤（臂）是一种侵略性的软组织 在儿童和年轻人中发生横纹肌谱系的肿瘤。 该癌症与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融合产品。检测这些融合 肿瘤标本，聚合酶链反应，原位杂交和南部 已经制定了印迹策略。使用这些测定，组间 横纹肌肉瘤研究小组（IRSG）试点研究提供了证据表明 这些基因融合是武器诊断的特定标记， PAX3-FKHR和PAX＆-FKHR子类型与手臂的不同结果有关 患者，高灵敏度测定能够在临床上检测 明显的亚显微镜转移性疾病。此外，最近的研究 建议在不在武器案例中存在其他融合亚型 可检测到典型的PAX3-FKHR或PAX7-FKHR融合转录本。这 初步研究支持融合基因检测的假设 武器的诊断，监测和管理中的重要作用 患者。进一步探讨这一假设 多机构的临床试验，经过统一治疗和诊断 患者和中央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 患者的生物学参数前瞻性地接受了IRS-V研究。 原发性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武器管理中的预测价值。 融合负臂肿瘤将研究变异和神秘基因 融合以建立其他融合类别以供这些融合类别 临床相关研究。骨髓和外周血标本 这些患者也将被分析以确定 转移性部位的亚镜疾病检测。最后，生物学 将检查增殖和凋亡状态的标记以确定 它们与这些患者的融合亚型和其他参数的关系。 这些研究将对发生的明确分析和临床分析 这些遗传改变在武器中的意义，并最终会影响 关于未来的临床方案，用于治疗武器患者。