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基于多组学的高级别浆液性卵巢癌亚型分析揭示了与患者预后相关的不同分子过程。

Multi-omics-based analysis of high grade serous ovarian cancer subtypes reveals distinct molecular processes linked to patient prognosis.

机构信息

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

出版信息

FEBS Open Bio. 2023 Apr;13(4):617-637. doi: 10.1002/2211-5463.13553. Epub 2023 Feb 24.

Abstract

Despite advancements in treatment, high-grade serous ovarian cancer (HGSOC) is still characterized by poor patient outcomes. To understand the molecular heterogeneity of this disease, which underlies the challenge in selecting optimal treatments for HGSOC patients, we have integrated genomic, transcriptomic, and epigenetic information to identify seven new HGSOC subtypes using a multiscale clustering method. These subtypes not only have significantly distinct overall survival, but also exhibit unique patterns of gene expression, microRNA expression, DNA methylation, and copy number alterations. As determined by our analysis, patients with similar clinical outcomes have distinct profiles of activated or repressed cellular processes, including cell cycle, epithelial-to-mesenchymal transition, immune activation, interferon response, and cilium organization. Furthermore, we performed a multiscale gene co-expression network analysis to identify subtype-specific key regulators and predicted optimal targeted therapies based on subtype-specific gene expression. In summary, this study provides new insights into the cellular heterogeneity of the HGSOC genomic, epigenetic, and transcriptomic landscapes and provides a basis for future studies into precision medicine for HGSOC patients.

摘要

尽管在治疗方面取得了进展,但高级别浆液性卵巢癌(HGSOC)仍然以患者预后不良为特征。为了了解这种疾病的分子异质性,这是为 HGSOC 患者选择最佳治疗方法的挑战的基础,我们整合了基因组、转录组和表观遗传信息,使用多尺度聚类方法鉴定了七个新的 HGSOC 亚型。这些亚型不仅具有显著不同的总生存期,而且还表现出独特的基因表达、microRNA 表达、DNA 甲基化和拷贝数改变模式。根据我们的分析,具有相似临床结局的患者具有不同的激活或抑制细胞过程的特征,包括细胞周期、上皮-间充质转化、免疫激活、干扰素反应和纤毛组织。此外,我们进行了多尺度基因共表达网络分析,以鉴定亚型特异性关键调节剂,并根据亚型特异性基因表达预测最佳靶向治疗。总之,这项研究深入了解了 HGSOC 基因组、表观基因组和转录组景观的细胞异质性,并为未来针对 HGSOC 患者的精准医学研究提供了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0301/10068328/893dbe9ef437/FEB4-13-617-g002.jpg

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