Cancer Res Treat.  2024 Oct;56(4):975-990. 10.4143/crt.2024.154.

Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency

• Kim YN
• Gulhan DC
• Jin H
• Glodzik D
• Park PJ

• KMID: 2560234
• DOI: http://doi.org/10.4143/crt.2024.154

Abstract

Accurate detection of homologous recombination deficiency (HRD) in cancer patients is paramount in clinical applications, as HRD confers sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. With the advances in genome sequencing technology, mutational profiling on a genome-wide scale has become readily accessible, and our knowledge of the genomic consequences of HRD has been greatly expanded and refined. Here, we review the recent advances in HRD detection methods. We examine the copy number and structural alterations that often accompany the genome instability that results from HRD, describe the advantages of mutational signature-based methods that do not rely on specific gene mutations, and review some of the existing algorithms used for HRD detection. We also discuss the choice of sequencing platforms (panel, exome, or whole-genome) and catalog the HRD detection assays used in key PARP inhibitor trials.

Keyword

Genomic instability; Mutational signature analysis; DNA repair; Copy number analysis; Poly(ADP-ribose) polymerase inhibitors

Figure

• 

  Fig. 1. Schematic summary of signature analysis in the context of homologous recombination deficient (HRD). (A) The process of double-strand break and repair. In HRD cells, homologous recombination—a high-fidelity repair mechanism—is dysfunctional, and thus errorprone mechanisms dominate. (B) Different types of genomic alterations, SBS, insertions/deletions (ID), CNV, and SV can be used to detect HRD. Spectra indicates typical mutational patterns associated with each alteration type, and among these spectra, HRD-associated signatures and their underlying etiology has been suggested. (C) Schematic description of mutational signature approach, which involves non-negative matrix factorization (NMF) on the mutation type-by-sample matrix, to identify the building blocks (i.e., signatures) that best summarize the data. (D) HRD detection based on CNV and SV-based raw traits that do not involve signature analysis. BIR, break-induced repair; LOH, loss of heterozygosity; LST, large-scale state transitions; MMEJ, microhomology-mediated end joining; NHEJ, nonhomologous end joining; rDel, reciprocal deletion; rDup, reciprocal duplication; SSA, single-strand annealing; tAI, telomeric allelic imbalance.

Reference

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