Greenwood Genetic Center, Greenwood, SC 29646, USA.
Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Genes (Basel). 2023 Aug 25;14(9):1683. doi: 10.3390/genes14091683.
Homologous recombination deficiency (HRD) is characterized by the inability of a cell to repair the double-stranded breaks using the homologous recombination repair (HRR) pathway. The deficiency of the HRR pathway results in defective DNA repair, leading to genomic instability and tumorigenesis. The presence of HRD has been found to make tumors sensitive to ICL-inducing platinum-based therapies and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi). However, there are no standardized methods to measure and report HRD phenotypes. Herein, we compare optical genome mapping (OGM), chromosomal microarray (CMA), and a 523-gene NGS panel for HRD score calculations. This retrospective study included the analysis of 196 samples, of which 10 were gliomas, 176 were hematological malignancy samples, and 10 were controls. The 10 gliomas were evaluated with both CMA and OGM, and 30 hematological malignancy samples were evaluated with both the NGS panel and OGM. To verify the scores in a larger cohort, 135 cases were evaluated with the NGS panel and 71 cases with OGM. The HRD scores were calculated using a combination of three HRD signatures that included loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST). In the ten glioma cases analyzed with OGM and CMA using the same DNA (to remove any tumor percentage bias), the HRD scores (mean ± SEM) were 13.2 (±4.2) with OGM compared to 3.7 (±1.4) with CMA. In the 30 hematological malignancy cases analyzed with OGM and the 523-gene NGS panel, the HRD scores were 7.6 (±2.2) with OGM compared to 2.6 (±0.8) with the 523-gene NGS panel. OGM detected 70.8% and 66.8% of additional variants that are considered HRD signatures in gliomas and hematological malignancies, respectively. The higher sensitivity of OGM to capture HRD signature variants might enable a more accurate and precise correlation with response to PARPi and platinum-based drugs. This study reveals HRD signatures that are cryptic to current standard of care (SOC) methods used for assessing the HRD phenotype and presents OGM as an attractive alternative with higher resolution and sensitivity to accurately assess the HRD phenotype.
同源重组缺陷 (HRD) 的特征是细胞无法使用同源重组修复 (HRR) 途径修复双链断裂。HRR 途径的缺陷导致 DNA 修复缺陷，导致基因组不稳定和肿瘤发生。已经发现 HRD 使肿瘤对 ICL 诱导的铂类治疗和聚（腺苷二磷酸 [ADP]-核糖）聚合酶 (PARP) 抑制剂 (PARPi) 敏感。然而，目前尚无测量和报告 HRD 表型的标准化方法。在此，我们比较了光学基因组图谱 (OGM)、染色体微阵列 (CMA) 和 523 基因 NGS 面板用于 HRD 评分计算。这项回顾性研究包括对 196 个样本的分析，其中 10 个为胶质瘤，176 个为血液恶性肿瘤样本，10 个为对照。10 个胶质瘤用 CMA 和 OGM 进行了评估，30 个血液恶性肿瘤样本用 NGS 面板和 OGM 进行了评估。为了在更大的队列中验证评分，用 NGS 面板评估了 135 例，用 OGM 评估了 71 例。HRD 评分使用包括杂合性缺失 (LOH)、端粒等位基因失衡 (TAI) 和大规模转换 (LST) 的三种 HRD 特征的组合进行计算。在使用相同 DNA（消除任何肿瘤百分比偏差）分析的 10 个 OGM 和 CMA 胶质瘤病例中，OGM 的 HRD 评分（平均值±SEM）为 13.2（±4.2），而 CMA 的 HRD 评分为 3.7（±1.4）。在使用 OGM 和 523 基因 NGS 面板分析的 30 个血液恶性肿瘤病例中，OGM 的 HRD 评分为 7.6（±2.2），而 523 基因 NGS 面板的 HRD 评分为 2.6（±0.8）。OGM 检测到了 70.8%和 66.8%的胶质瘤和血液恶性肿瘤中分别被认为是 HRD 特征的额外变体。OGM 捕获 HRD 特征变体的更高敏感性可能能够更准确和精确地与 PARPi 和铂类药物的反应相关联。本研究揭示了目前用于评估 HRD 表型的标准护理 (SOC) 方法所隐藏的 HRD 特征，并提出了 OGM 作为一种有吸引力的替代方法，具有更高的分辨率和灵敏度，可准确评估 HRD 表型。
