Kechin Andrey, Koryukov Maksim, Mikheeva Regina, Filipenko Maksim
Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, 630090, Russia.
Novosibirsk State University, Novosibirsk, 630090, Russia.
Cancer Metastasis Rev. 2024 Dec 26;44(1):19. doi: 10.1007/s10555-024-10238-y.
Homologous recombination deficiency (HRD) is considered a universal and effective sign of a tumor's sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. HRD diagnostics have undergone several stages of transformations: from detection of point mutations in HR-related genes and large regions with loss of heterozygosity detected using single-nucleotide polymorphism arrays to whole-genome signatures of single-nucleotide variants, large genomic rearrangements (LGRs), and copy number alterations. All these methods have their own advantages and limitations. HRD tests, based on signatures of LGRs and copy number alterations, show in hindsight that some progenitor cells have possessed HRD status but not the current state of the genome. The aim of this review was to compare different methods of HRD detection and mechanisms of formation of HRD-specific LGRs. In the last several years, new data appeared implying a crucial role of proteins BRCA1 and BRCA2 in the resolution of stalled replication forks that may be associated with at least some of LGRs observed in HRD-positive tumors. Reviewing current knowledge on these mechanisms, distributions of different LGR types, and limitations of sequencing technologies and algorithms of data analysis, we offer some new perspectives on HRD diagnostics. We hope that this review will help to accelerate the development of new diagnostic approaches in this important field of molecular oncology.
同源重组缺陷（HRD）被认为是肿瘤对聚（ADP-核糖）聚合酶（PARP）抑制剂敏感性的一个普遍且有效的标志。HRD诊断已经历了几个阶段的转变：从检测HR相关基因中的点突变以及使用单核苷酸多态性阵列检测杂合性缺失的大片段区域，到单核苷酸变异、大基因组重排（LGR）和拷贝数改变的全基因组特征。所有这些方法都有其自身的优点和局限性。基于LGR和拷贝数改变特征的HRD检测事后显示，一些祖细胞具有HRD状态，但并非当前的基因组状态。本综述的目的是比较不同的HRD检测方法以及HRD特异性LGR的形成机制。在过去几年中，新的数据表明，BRCA1和BRCA2蛋白在停滞复制叉的修复中起关键作用，这可能与在HRD阳性肿瘤中观察到的至少一些LGR相关。回顾关于这些机制、不同LGR类型的分布以及测序技术和数据分析算法的局限性的现有知识，我们提供了一些关于HRD诊断的新观点。我们希望本综述将有助于加速这一分子肿瘤学重要领域新诊断方法的发展。
