Homologous recombination repair deficiency (HRD) results in a defect in DNA repair and is a frequent driver of tumorigenesis. Poly(ADP-ribose) polymerase inhibitors (PARPi) or platinum-based therapies have increased theraputic effectiveness when treating HRD positive cancers. For breast cancer and ovairan cancer HRD companion diagnostic tests are commonly used. However, the currently used HRD tests are based on high-depth genome sequencing or hybridization-based capture sequencing, which are technically complex and costly. In this study, we modified an existing method named shallowHRD, which uses low-pass whole genome sequencing (WGS) for HRD detection, and estimated the performance of the modified shallowHRD pipeline. Our shallowHRD pipeline achieved an AUC of 0.997 in simulated low-pass WGS data, with a sensitivity of 0.981 and a specificity of 0.964; and achieved a higher HRD risk score in clinical BRCA-deficient breast cancer samples (p = 5.5 × 10⁻⁵, compared with BRCA-intact breast cancer samples). We also estimated the limit of detection the shallowHRD pipeline could accurately predict HRD status with a minimum sequencing depth of 0.1 ×, a tumor purity of > 20%, and an input DNA amount of 1 ng. Our study demostrates using low-pass sequencing, HRD status can be determined with high accuracy using a simple approach with greatly reduced cost.

同源重组修复缺陷 (HRD) 导致 DNA 修复缺陷，是肿瘤发生的常见驱动因素。聚（ADP-核糖）聚合酶抑制剂 (PARPi) 或铂类疗法在治疗 HRD 阳性癌症时提高了治疗效果。对于乳腺癌和卵巢癌，通常使用 HRD 伴随诊断测试。然而，目前使用的HRD测试是基于高深度基因组测序或基于杂交的捕获测序，技术复杂且成本高。在这项研究中，我们修改了一种名为 shallowHRD 的现有方法，该方法使用低通全基因组测序 (WGS) 进行 HRD 检测，并评估了修改后的 shallowHRD 管道的性能。我们的 shallowHRD 管道在模拟的低通 WGS 数据中实现了 0.997 的 AUC，灵敏度为 0。981，特异性为 0.964；并在临床 BRCA 缺陷型乳腺癌样本中获得更高的 HRD 风险评分（p  = 5.5 × 10 ^-5，与 BRCA 完整乳腺癌样本相比）。我们还估计了 shallowHRD 管道可以准确预测 HRD 状态的检测限，最小测序深度为 0.1 ×，肿瘤纯度 > 20%，输入 DNA 量为 1 ng。我们的研究表明，使用低通测序，可以使用一种简单的方法以大大降低的成本高精度地确定 HRD 状态。