骨肉瘤(OS)是最常见的骨肿瘤,但是在解开涉及其启动和进展的全套基因组事件方面取得了缓慢的进展。我们通过NGS评估了来自巴西患者的28个主要OS的突变谱,并鉴定出445个潜在有害的SNV/indel和1176个拷贝数改变(CNA)。TP53是最常见的突变基因,总体比率约为60%,考虑SNV/indel和CNAs。最常见的CNAs(约60%)是1q21.2q21.3、6p21.1和8q13.3q24.22的涨幅,以及10q26和13q14.3q21.1的跌幅。7例出现CNA模式,让人联想到复杂事件(色素沉着和色素沉着)。在诊断时与转移相关的五个样品中发现了推定的RB1和TP53种系变体以及CNA的复杂基因组模式。PTPRQ,KNL1、ZFHX4和DMD改变在转移或死亡患者中普遍存在,可能表明预后不良。TNFRSF11B,参与骨骼系统的开发和维护,由于其生物学功能和高拷贝数增加的频率,成为骨分化的候选者。蛋白质-蛋白质网络富集突出了参与免疫和骨骼发育的生物学途径。我们的发现加强了高基因组OS不稳定性和异质性,并导致鉴定了新的破坏基因,由于它们与不良结局相关,值得作为生物标志物进行进一步评估。
Osteosarcoma (OS) is the most prevalent type of bone tumor, but slow progress has been achieved in disentangling the full set of genomic events involved in its initiation and progression. We assessed by NGS the mutational spectrum of 28 primary OSs from Brazilian patients, and identified 445 potentially deleterious SNVs/indels and 1176 copy number alterations (CNAs). TP53 was the most recurrently mutated gene, with an overall rate of ~60%, considering SNVs/indels and CNAs. The most frequent CNAs (~60%) were gains at 1q21.2q21.3, 6p21.1, and 8q13.3q24.22, and losses at 10q26 and 13q14.3q21.1. Seven cases presented CNA patterns reminiscent of complex events (chromothripsis and
chromoanasynthesis). Putative RB1 and TP53 germline variants were found in five samples associated with metastasis at diagnosis along with complex genomic patterns of CNAs. PTPRQ, KNL1, ZFHX4, and DMD alterations were prevalent in metastatic or deceased patients, being potentially indicative of poor prognosis. TNFRSF11B, involved in skeletal system development and maintenance, emerged as a candidate for osteosarcomagenesis due to its biological function and a high frequency of copy number gains. A protein-protein network enrichment highlighted biological pathways involved in immunity and bone development. Our findings reinforced the high genomic OS instability and heterogeneity, and led to the identification of novel disrupted genes deserving further evaluation as biomarkers due to their association with poor outcomes.