■骨肿瘤,骨肉瘤,在儿童和年轻人中治疗仍然具有挑战性,尤其是当患者出现转移性疾病时。鉴于肿瘤中缺乏复发性遗传损伤,基于测序项目的基因组数据开发新的疗法已被证明是困难的。MYC过表达与骨肉瘤的不良预后相关。然而,缺乏其他疾病严重程度的基因组标记.
我们利用106个肿瘤和匹配的正常对照的全基因组测序来定义与总存活相关的基因组特征。将单核苷酸变体覆盖到注释的分子途径上,以定义对侵袭性骨肉瘤特异的异常途径特征。此外,我们计算了71个肿瘤的子样本中的差异基因表达。然后针对已知的MYC应答基因查询差异表达的基因。
■核孔复合体分解(NPCD)的特异性分子通路显示,当存在突变时,骨肉瘤的总体生存率很低。在具有和不具有NPCD途径畸变的样品的差异表达分析中富集了参与免疫应答和免疫调节的基因。此外,MYC和MYC反应基因均未显示NPCD异常组和非异常组之间的差异表达。NPCD通路突变主要由调节区变体而不是蛋白质改变突变主导。提示遗传调控网络的失调可能是其与骨肉瘤表型相关的潜在机制。
■肿瘤显示NPCD通路异常的患者总生存期明显较差。此外,这种存活率的差异不是由MYC过表达引起的,提示一些侵袭性骨肉瘤的新机制。这些发现为对骨肉瘤驱动因素的不断发展的理解增添了光明,并可能有助于基于患者特异性遗传数据寻找新的治疗方法。
UNASSIGNED: The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking.
UNASSIGNED: We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes.
UNASSIGNED: Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype.
UNASSIGNED: Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data.