TY - JOUR

T1 - Homologous recombination deficiency (HRD) diagnostics: underlying mechanisms and new perspectives

AU - Kechin, Andrey

AU - Koryukov, Maksim

AU - Mikheeva, Regina

AU - Filipenko, Maksim

N1 - Funding The work was supported by Russian Science Foundation grant No. 23–74-01138 “New algorithms for detecting large genomic rearrangements to diagnose homologous recombination deficiency.”

PY - 2025

Y1 - 2025

N2 - Homologous recombination deficiency (HRD) is considered a universal and effective sign of a tumor’s sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. HRD diagnostics have undergone several stages of transformations: from detection of point mutations in HR-related genes and large regions with loss of heterozygosity detected using single-nucleotide polymorphism arrays to whole-genome signatures of single-nucleotide variants, large genomic rearrangements (LGRs), and copy number alterations. All these methods have their own advantages and limitations. HRD tests, based on signatures of LGRs and copy number alterations, show in hindsight that some progenitor cells have possessed HRD status but not the current state of the genome. The aim of this review was to compare different methods of HRD detection and mechanisms of formation of HRD-specific LGRs. In the last several years, new data appeared implying a crucial role of proteins BRCA1 and BRCA2 in the resolution of stalled replication forks that may be associated with at least some of LGRs observed in HRD-positive tumors. Reviewing current knowledge on these mechanisms, distributions of different LGR types, and limitations of sequencing technologies and algorithms of data analysis, we offer some new perspectives on HRD diagnostics. We hope that this review will help to accelerate the development of new diagnostic approaches in this important field of molecular oncology.

AB - Homologous recombination deficiency (HRD) is considered a universal and effective sign of a tumor’s sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. HRD diagnostics have undergone several stages of transformations: from detection of point mutations in HR-related genes and large regions with loss of heterozygosity detected using single-nucleotide polymorphism arrays to whole-genome signatures of single-nucleotide variants, large genomic rearrangements (LGRs), and copy number alterations. All these methods have their own advantages and limitations. HRD tests, based on signatures of LGRs and copy number alterations, show in hindsight that some progenitor cells have possessed HRD status but not the current state of the genome. The aim of this review was to compare different methods of HRD detection and mechanisms of formation of HRD-specific LGRs. In the last several years, new data appeared implying a crucial role of proteins BRCA1 and BRCA2 in the resolution of stalled replication forks that may be associated with at least some of LGRs observed in HRD-positive tumors. Reviewing current knowledge on these mechanisms, distributions of different LGR types, and limitations of sequencing technologies and algorithms of data analysis, we offer some new perspectives on HRD diagnostics. We hope that this review will help to accelerate the development of new diagnostic approaches in this important field of molecular oncology.

KW - BRCA1

KW - BRCA2

KW - Cancer

KW - PARP inhibitor

KW - Replication restart

UR - https://www.mendeley.com/catalogue/b562d269-e027-3244-a2de-e70fbf5a171c/

UR - https://pubmed.ncbi.nlm.nih.gov/39724448/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85213011875&origin=inward&txGid=5f9de33edccbf1a2fa4e6d8906eacaf6

U2 - 10.1007/s10555-024-10238-y

DO - 10.1007/s10555-024-10238-y

M3 - Article

C2 - 39724448

VL - 44

JO - Cancer and Metastasis Reviews

JF - Cancer and Metastasis Reviews

SN - 1573-7233

IS - 1

ER -