Zhao Qianying, Bai Liping, Tan Yu, Qie Mingrong
Department of Medical Genetics/Prenatal Diagnostic Center, West China Second University Hospital, Sichuan University, Chengdu, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
Front Oncol. 2024 Jul 22;14:1435029. doi: 10.3389/fonc.2024.1435029. eCollection 2024.
Homologous recombination (HR) is a highly conserved DNA repair system, in which aberrations can lead to the accumulation of DNA damage and genomic scars known as homologous recombination deficiency (HRD). The identification of mutations in key genes (i.e., , and (BRCA)) and the quantification of large-scale structural variants (e.g., loss of heterozygosity) are indicators of the HRD phenotype. HRD is a stable biomarker and remains unchanged during recurrence, but fails to reveal the molecular profile of tumor progression. Moreover, interpretation of the current HRD score lacks comprehensiveness, especially for the HR-proficient group. Poly (ADP-ribose) polymerase (PARP) enzymes play an important role in the repair of DNA single-strand breaks, the blockage of which using PARP inhibitors (PARPi) can generate synthetic lethality in cancer cells with HRD. Although numerous studies have demonstrated that the benefit of PARPi is substantial in ovarian cancer (OC) patients, the efficacy is limited by the development of resistance, and seems to be irrespective of HR and/or BRCA mutation status. Moreover, in addition to improving progression-free survival, long-term benefit as overall survival brought by PARPi for advanced, recurrent and refractory OC patients remains unclear. Therefore, further investigations are needed to uncover the role of HR genes beyond BRCA and their interactions with other oncogenic pathways, to determine the value of HRD in the recurrent setting, and to identify alternative strategies for the precise management of advanced, refractory OC patients.
同源重组（HR）是一种高度保守的DNA修复系统，其中的异常可导致DNA损伤和被称为同源重组缺陷（HRD）的基因组疤痕的积累。关键基因（即 、 和 （BRCA））突变的鉴定以及大规模结构变异（如杂合性缺失）的定量是HRD表型的指标。HRD是一种稳定的生物标志物，在复发过程中保持不变，但无法揭示肿瘤进展的分子特征。此外，目前HRD评分的解释缺乏全面性，特别是对于HR功能正常的组。聚（ADP-核糖）聚合酶（PARP）酶在DNA单链断裂修复中起重要作用，使用PARP抑制剂（PARPi）阻断该过程可在具有HRD的癌细胞中产生合成致死性。尽管大量研究表明PARPi对卵巢癌（OC）患者有显著益处，但其疗效受到耐药性发展的限制，且似乎与HR和/或BRCA突变状态无关。此外，除了改善无进展生存期外，PARPi对晚期、复发和难治性OC患者带来的作为总生存期的长期益处仍不清楚。因此，需要进一步研究以揭示BRCA以外的HR基因的作用及其与其他致癌途径的相互作用，确定HRD在复发情况下的价值，并确定对晚期、难治性OC患者进行精准管理的替代策略。
