Homologous recombination deficiency prediction using low-pass whole genome sequencing in breast cancer

作者：Liu, Yang; Li, Yalun; Zhang, Min-Zhe; Chen, Dan; Leng, Yang; Wang, Juan; Han, Bo-Wei^*; Wang, Ji

来源：CANCER GENETICS, 2023, 272: 1-6.

DOI：10.1016/j.cancergen.2023.02.001

• Homologous recombination repair
• deficiency
• Whole genome sequencing
• Copy number variations
• Breast cancer

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 can-cer 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 com-plex 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 shal-lowHRD 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 x 10 -5, compared with BRCA-intact breast cancer sam-ples). We also estimated the limit of detection the shallowHRD pipeline could accurately predict HRD status with a minimum sequencing depth of 0.1 x, 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.

• 单位
  哈尔滨医科大学