Decoding the Genomic and Functional Landscape of Emerging Subtypes in Ovarian Cancer.

IF 33.3 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-07-31 DOI:10.1158/2159-8290.cd-25-0652

Giulia Micoli,Kari Lavikka,Yilin Li,Anna Pirttikoski,Daria Afenteva,Wojciech Senkowski,Giovanni Marchi,Anna Vaharautio,Taru A Muranen,Titta Joutsiniemi,Sakari Hietanen,Anni Virtanen,Krister Wennerberg,Johanna Hynninen,Jaana Oikkonen,Sampsa Hautaniemi

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引用次数: 0

Abstract

Ovarian high-grade serous carcinoma (HGSC) is characterized by pervasive genomic instability and high inter- and intra-tumor heterogeneity. Approximately half of HGSC tumors harbor homologous recombination deficiency (HRD), rendering them vulnerable to PARP inhibitors and platinum-based chemotherapy. In contrast, patients lacking HRD (HR-proficient, HRP) generally respond poorly to the current therapies. To overcome heterogeneity and identify relevant HGSC subtypes, we characterized the genomic landscape of 640 tumors from 243 patients using whole-genome sequencing. Our chromosomal instability (CIN) signature-based analysis characterized the structural variation landscape and revealed five HGSC subtypes, validated in an independent dataset. Two HRD subtypes, associated with BRCA1- or BRCA2-driven alterations, demonstrated favorable treatment responses. Strikingly, three HRP subtypes emerged, marked by unique structural alterations and gene expression patterns, tumor microenvironment interactions, and different chemotherapy responses. Finally, organoid experiments showed subtype-specific sensitivity to CHK1 inhibition, suggesting prexasertib as a potential targeted treatment for most currently untreatable HRP patients.

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解码卵巢癌新亚型的基因组和功能景观。

卵巢高级别浆液性癌（HGSC）的特点是普遍的基因组不稳定性和肿瘤间和肿瘤内的高度异质性。大约一半的HGSC肿瘤具有同源重组缺陷（HRD），使其对PARP抑制剂和铂基化疗易感。相比之下，缺乏HRD （hr -精通，HRP）的患者通常对目前的治疗反应较差。为了克服异质性并确定相关的HGSC亚型，我们使用全基因组测序对来自243例患者的640个肿瘤的基因组图谱进行了表征。我们基于染色体不稳定性（CIN）特征的分析表征了结构变化景观，并揭示了五种HGSC亚型，在一个独立的数据集中得到了验证。两种HRD亚型，与BRCA1或brca2驱动的改变相关，显示出良好的治疗反应。引人注目的是，出现了三种HRP亚型，其特征是独特的结构改变和基因表达模式、肿瘤微环境相互作用和不同的化疗反应。最后，类器官实验显示对CHK1抑制的亚型特异性敏感性，提示prexasertib是目前大多数无法治疗的HRP患者的潜在靶向治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.