Shah Bhaumik, Hussain Muhammad, Seth Anjali
Department of Pathology, Fox Chase Cancer Center, Temple Health, Philadelphia, PA 19121, USA.
Department of Pathology, Temple University Hospital, Temple Health, 3401 N Broad St., Philadelphia, PA 19140, USA.
Curr Issues Mol Biol. 2025 Aug 8;47(8):638. doi: 10.3390/cimb47080638.
Homologous recombination deficiency (HRD) is a pivotal biomarker in precision oncology, driving therapeutic strategies for ovarian and breast cancers through impaired DNA double-strand break repair. This narrative review synthesizes recent advances (2021-2025) in HRD's biological basis, prevalence, detection methods, and clinical implications, focusing on high-grade serous ovarian carcinoma (HGSOC; ~50% HRD prevalence) and triple-negative breast cancer (TNBC; 50-70% prevalence). HRD arises from genetic (, , ) and epigenetic alterations (e.g., methylation), leading to genomic instability detectable via scars (LOH, TAI, LST) and mutational signatures (e.g., COSMIC SBS3). Advanced detection integrates genomic assays (Myriad myChoice CDx, Caris HRD, FoundationOne CDx), functional assays (RAD51 foci), and epigenetic profiling, with tools like HRProfiler and GIScar achieving >90% sensitivity. HRD predicts robust responses to PARP inhibitors (PARPi) and platinum therapies, extending progression-free survival by 12-36 months in HGSOC. However, resistance mechanisms ( reversion, , ) and assay variability (60-70% non- concordance) pose challenges. We propose a conceptual framework in , integrating multi-omics, methylation analysis, and biallelic reporting to enhance detection and therapeutic stratification. Regional variations (e.g., Asian cohorts) and disparities in access underscore the need for standardized, cost-effective diagnostics. Future priorities include validating novel biomarkers (SBS39, miR-622) and combination therapies (PARPi with ATR inhibitors) to overcome resistance and broaden HRD's applicability across cancers.
同源重组缺陷（HRD）是精准肿瘤学中的一个关键生物标志物，通过受损的DNA双链断裂修复推动卵巢癌和乳腺癌的治疗策略。本叙述性综述综合了HRD在生物学基础、患病率、检测方法和临床意义方面的最新进展（2021 - 2025年），重点关注高级别浆液性卵巢癌（HGSOC；HRD患病率约50%）和三阴性乳腺癌（TNBC；患病率50 - 70%）。HRD源于基因（，，）和表观遗传改变（例如，甲基化），导致可通过疤痕（杂合性缺失、端粒等位基因不平衡、大片段状态改变）和突变特征（例如，COSMIC SBS3）检测到的基因组不稳定。先进的检测方法整合了基因组检测（Myriad myChoice CDx、Caris HRD、FoundationOne CDx）、功能检测（RAD51灶）和表观遗传分析，像HRProfiler和GIScar这样的工具灵敏度达到>90%。HRD预测对PARP抑制剂（PARPi）和铂类疗法有强烈反应，在HGSOC中可将无进展生存期延长12 - 36个月。然而，耐药机制（回复突变、，）和检测变异性（60 - 70%不一致）带来了挑战。我们在中提出了一个概念框架，整合多组学、甲基化分析和双等位基因报告以加强检测和治疗分层。地区差异（例如亚洲队列）和获取机会的不平等凸显了标准化、经济有效的诊断方法的必要性。未来的优先事项包括验证新型生物标志物（SBS39、miR - 622）和联合疗法（PARPi与ATR抑制剂）以克服耐药性并扩大HRD在各种癌症中的适用性。
