Highlights
- •HRD test is widely used for administrating PARPi chemotherapy in breast cancer.
- •Existing methods are either experimentally complicated or commercially expensive.
- •Low-pass WGS based HRD detection method performs well in breast cancer.
- •Present an HRD test with high accuracy, ease of operation, and acceptable cost.
Abstract
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.
Keywords
Abbreviations:
HRD (Homologous recombination deficiency), HRR (Homologous recombination repair), PARPi (Poly(ADP-ribose) polymerase inhibitors), WGS (Whole genome sequencing), CNV (Copy number variation), LGA (Large-scale genomic alterations), PBMC (Peripheral blood mononuclear cell), FFPE (Formalin-fixed paraffin-embedded), ROC (Receiver operating characteristic), AUC (Area under the curve)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: February 03, 2023
Accepted:
February 2,
2023
Received in revised form:
January 17,
2023
Received:
September 22,
2022
Identification
Copyright
© 2023 Elsevier Inc. All rights reserved.
