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在乳腺癌中同源重组缺陷的多尺度表征

Daniel H Jacobson^1,2, Shi Pan¹, Jasmin Fisher²

¹UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, Gower Street, London, WC1E 6BT, UK.

Genome medicine

|November 3, 2023

概括

乳腺癌中的同源重组缺陷 (HRD) 可以通过小插入/删除事件更好地分类. 一个新的转录特征揭示了HRD异质性及其对瘤微环境的影响,有助于PARP抑制剂反应预测.

科学领域:

基因组学和分子生物学
癌症研究癌症研究
生物信息学是一种生物信息学.

背景情况:

同源重组 (HR) 是一种关键的DNA修复途径;缺陷 (HRD) 与PARP抑制剂敏感性有关.
目前的方法用于识别HRD使用突变签名从外基因组测序的精度和时间相关性有局限性.
了解HRD异质性对于有效的癌症治疗策略至关重要.

研究的目的:

开发和验证用于表征乳腺癌同源复合缺陷 (HRD) 的新方法.
探索人力资源发展的异质性及其与瘤微环境相互作用的关联.
为了识别可预测HRD状态和PARP抑制剂反应的转录特征.

主要方法:

开发一种基于概率的分类方法,利用从外因子测序数据中小插入和删除 (indel) 事件.
应用多项弹性净回归来创建异质HRD的转录签名.
在单细胞RNA测序数据上验证转录签名,以分析HRD异质性和瘤微环境交互性.

主要成果:

包含indel事件显著改善了在外体测序乳腺癌中HRD分类准确度.
开发了一种228基因的转录特征,能够表征HRD和BRCA1/2缺陷状态,并预测PARP抑制剂反应.
应用到单细胞数据的签名揭示了HRD细胞中独特的瘤微环境相互作用,包括对TNFα信号的改变反应.

结论:

结合突变和转录特征的多尺度方法提供了乳腺癌中HRD的强有力的特征.
从外体序列测序来改善HRD分类,indels是有价值的,而转录签名在单细胞水平上捕捉HRD异质性.
这些发现使得对DNA修复缺陷与瘤微环境之间的相互作用进行了更深入的研究,这对向治疗有意义.

关键词:

乳腺癌是什么? 乳腺癌是什么同类重组缺陷的同类重组缺陷突变的签名突变的签名抑制PARP的抑制作用一个单细胞的单细胞.转录分类器转录分类器瘤微环境中的微环境

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