Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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匹配的原发性和转移性小儿骨肉瘤的综合基因组分析。

尽管是最常见的儿童骨肿瘤，但骨肉瘤的基因组特征仍然不完整。特别是，迄今为止，很少有骨肉瘤转移被测序，这对于更好地了解这种肿瘤的进展和进化机制至关重要。我们对成对的原发性和转移性小儿骨肉瘤标本进行了整合的全基因组和外显子组测序分析，以确定复发性基因组改变。对 13 名骨肉瘤患者（包括 13 名原发性肿瘤、10 名转移性肿瘤和 3 名局部复发性肿瘤）的测序显示出高度异质的突变情况，包括高突变和微卫星不稳定性阳性病例，但除了涉及肿瘤抑制基因 RB1 和 TP53 的突变外，几乎没有复发性改变. 在种系水平，我们在大多数队列中检测到多个癌症相关基因的改变，包括那些可能破坏 DNA 损伤反应途径的基因。转移灶仅保留了来自其相应原发性肿瘤的最少数量的短变体，而拷贝数改变显示出更高的保守性。一种反复扩增的基因 KDR 在晚期病例中高度表达，并且与预后不良有关。© 2019 大不列颠及爱尔兰病理学会。约翰威利父子公司出版 在晚期病例中高度表达并与预后不良有关。© 2019 大不列颠及爱尔兰病理学会。约翰威利父子公司出版 在晚期病例中高度表达并与预后不良有关。© 2019 大不列颠及爱尔兰病理学会。约翰威利父子公司出版