Biomarkers for Homologous Recombination Deficiency in Cancer

2018/04/10 by Michal M Hoppe, Michał Marek Hoppe, Raghav Sundar +4 · 335 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Biology #CRISPR and Genetic Engineering #Computational biology #DNA #DNA Repair Mechanisms #DNA damage #DNA repair #Gene #Genetics #Genome instability #Germline mutation #Homologous chromosome #Homologous recombination #Mutation #PARP inhibition in cancer therapy #PARP inhibitor #Poly ADP ribose polymerase #Polymerase #RAD51

paper · pdf · doi:10.1093/jnci/djy085

published in JNCI Journal of the National Cancer Institute 110(7), 704-713 (Oxford University Press)

openalex publication_date 2018/04/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/02

Abstract

Defective DNA repair is a common hallmark of cancer. Homologous recombination is a DNA repair pathway of clinical interest due to the sensitivity of homologous recombination-deficient cells to poly-ADP ribose polymerase (PARP) inhibitors. The measurement of homologous recombination deficiency (HRD) in cancer is therefore vital to the appropriate design of clinical trials incorporating PARP inhibitors. However, methods to identify HRD in tumors are varied and controversial. Understanding existing and new methods to measure HRD is important to their appropriate use in clinical trials and practice. The aim of this review is to summarize the biology and clinical validation of current methods to measure HRD, to aid decision-making for patient stratification and translational research in PARP inhibitor trials. We discuss the current clinical development of PARP inhibitors, along with established indicators for HRD such as germline BRCA1/2 mutation status and clinical response to platinum-based therapy. We then examine newer assays undergoing clinical validation, including 1) somatic mutations in homologous recombination genes, 2) "genomic scar" assays using array-based comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) analysis or mutational signatures derived from next-generation sequencing, 3) transcriptional profiles of HRD, and 4) phenotypic or functional assays of protein expression and localization. We highlight the strengths and weaknesses of each of these assays, for consideration during the design of studies involving PARP inhibitors.

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