Subclonal Somatic Copy-Number Alterations Emerge and Dominate in Recurrent Osteosarcoma.
Subclonal Somatic Copy-Number Alterations Emerge and Dominate in Recurrent Osteosarcoma.
复制标题
DOI：
10.1158/0008-5472.can-23-0385
复制
发表时间：
2023-11-15
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
--
作者：
复发性骨肉瘤的化疗耐药人群在诊断时是亚克隆的，由于新辅助化疗的选择性压力，在初次切除时出现，其特征是独特的致癌基因扩增。已经在骨肉瘤中进行了多个大规模基因组分析，以确定肿瘤发生、治疗反应和疾病复发的基因组驱动因素。肿瘤内的空间和时间异质性也可能在促进肿瘤生长和治疗抵抗中发挥作用。我们对8例复发性或难治性骨肉瘤患者的37个肿瘤样本进行了纵向全基因组测序。每例患者至少有一个来自原发部位和转移或复发部位的样本。除1例患者外，所有患者均发现亚克隆拷贝数改变。在5例患者中，原发肿瘤的亚克隆出现并在随后的复发中占主导地位。MYC获得/扩增在7例具有多个克隆的患者中的6例中的治疗抗性克隆中富集。在其他潜在的驱动基因，如CCNE 1，RAD 21，VEGFA和IGF 1 R，也观察到在耐药拷贝数克隆的扩增。染色体重复定时分析显示，复杂的基因组重排通常发生在诊断之前，支持进化的宏观进化模型，其中大量的基因组畸变在短时间内获得，随后进行克隆选择，而不是持续的进化。复发性肿瘤的突变特征分析显示，在复发性疾病患者中，同源修复缺陷（HRD）相关的SBS 3在每个时间点增加，表明HRD在诊断后仍然是一个活跃的致突变过程。总的来说，通过检查复发性/难治性骨肉瘤患者的时间和空间分离样本之间的克隆关系，这项研究揭示了肿瘤内异质性和这种疾病治疗耐药性的潜在驱动因素。复发性骨肉瘤的化疗耐药人群在诊断时是亚克隆的，由于新辅助化疗的选择性压力，在初次切除时出现，其特征是独特的致癌基因扩增。
The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications. Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease. The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
跨物种基因组学鉴定 DLG2 作为骨肉瘤的肿瘤抑制因子
影响因子：
8
作者：
Shao YW;Wood GA;Lu J;Tang QL;Liu J;Molyneux S;Chen Y;Fang H;Adissu H;McKee T;Waterhouse P;Khokha R
通讯作者：
Khokha R