Abstract：
Osteosarcoma is a primary bone tumor that exhibits a complex genomic landscape characterized by gross chromosomal abnormalities. Osteosarcoma patients often develop metastatic disease, resulting in limited therapeutic options and poor survival rates. To gain knowledge on the mechanisms underlying osteosarcoma heterogeneity and metastatic process, it is important to obtain a detailed profile of the genomic alterations that accompany osteosarcoma progression. We performed WGS on multiple tissue samples from six patients with osteosarcoma, including the treatment naïve biopsy of the primary tumor, resection of the primary tumor after neoadjuvant chemotherapy, local recurrence, and distant metastases. A comprehensive analysis of single-nucleotide variants (SNVs), structural variants, copy number alterations (CNAs), and chromothripsis events revealed the genomic heterogeneity during osteosarcoma progression. SNVs and structural variants were found to accumulate over time, contributing to an increased complexity of the genome of osteosarcoma during disease progression. Phylogenetic trees based on SNVs and structural variants reveal distinct evolutionary patterns between patients, including linear, neutral, and branched patterns. The majority of osteosarcomas showed variable copy number profiles or gained whole-genome doubling in later occurrences. Large proportions of the genome were affected by loss of heterozygosity (LOH), although these regions remain stable during progression. Additionally, chromothripsis is not confined to a single early event, as multiple other chromothripsis events may appear in later occurrences. Together, we provide a detailed analysis of the complex genome of osteosarcomas and show that five of six osteosarcoma genomes are highly dynamic and variable during progression.
摘要：
骨肉瘤是一种原发性骨肿瘤，表现出复杂的基因组景观，其特征是总体染色体异常。骨肉瘤患者经常发展为转移性疾病，导致有限的治疗选择和低生存率。为了了解骨肉瘤异质性和转移过程的潜在机制，重要的是获得伴随骨肉瘤进展的基因组改变的详细概况。我们对六名骨肉瘤患者的多个组织样本进行了WGS，包括原发肿瘤的原始活检治疗，新辅助化疗后切除原发肿瘤，局部复发,和远处转移。单核苷酸变异（SNV）的综合分析，结构变体，拷贝数变更(CNAs)，和染色体异常事件揭示了骨肉瘤进展过程中的基因组异质性。发现SNV和结构变体随着时间的推移而积累，在疾病进展过程中，骨肉瘤基因组的复杂性增加。基于SNV和结构变异的系统发育树揭示了患者之间不同的进化模式，包括线性，中性,和分枝的图案。大多数骨肉瘤显示出可变的拷贝数谱或在以后的发生中获得了全基因组加倍。大部分基因组受到杂合性缺失（LOH）的影响，尽管这些区域在进展期间保持稳定。此外,chromothripsis并不局限于一个早期事件，因为在以后的事件中可能会出现多个其他染色体事件。一起,我们对骨肉瘤的复杂基因组进行了详细的分析，并表明六个骨肉瘤基因组中有五个在进展过程中具有高度的动态性和可变性。
