Homologous Recombination Deficiency Scar: Mutations and Beyond—Implications for Precision Oncology

Abstract

Homologous recombination deficiency (HRD) is a prevalent in approximately 17% of tumors and is associated with enhanced sensitivity to anticancer therapies inducing double-strand DNA breaks. Accurate detection of HRD would therefore allow improved patient selection and outcome of conventional and targeted anticancer therapies. However, current clinical assessment of HRD mainly relies on determining germline BRCA1/2 mutational status and is insufficient for adequate patient stratification as mechanisms of HRD occurrence extend beyond functional BRCA1/2 loss. HRD, regardless of BRCA1/2 status, is associated with specific forms of genomic and mutational signatures termed HRD scar. Detection of this HRD scar might therefore be a more reliable biomarker for HRD. This review discusses and compares different methods of assessing HRD and HRD scar, their advances into the clinic, and their potential implications for precision oncology.

The Utility of Comprehensive NGS Analysis in Homologous Recombination Deficiency Tracking

“…Despite this, comprehensive NGS assays such as the one used in this study may be useful in providing additional clinically relevant tumor genomic information, since a single analysis provides results related to genomic scars such as LOH along with information concerning the mutational status of important targetable genes, including those of the HR pathways, tumor mutational burden, and microsatellite instability status. Besides such an approach can identify the concomitant presence of LOH and HR mutations in certain cases, which could be a more valuable predictive marker of PARPi sensitivity compared to the analysis of each of these events individually (10) Furthermore, in our cohort, no statistically significant association was observed in our cohort between LOH and other non-HR gene mutations or high TMB values. This is in agreement with other studies (27).…”

“…The existence of certain genomic scars in the tumor, suggesting underlying genomic instability, might be analyzed as a second method for assessing the impact of such abnormality on the genome. The genomic and transcriptome characteristics associated with the HRD phenotype, as well as functional tests such as the identification of RAD51 foci, have been developed to assess HRD consequences following a cellʹs exposure to a DNA damaging agent (9) The most common genomic scar assays reported to date are the analysis of the percentage of genomic regions with LOH or the combined use of LOH, telomeric allelic imbalance (TAI), and largescale transitions (LSTs), giving rise to a GI score (10)Two GI commercial tests have been extensively evaluated in clinical trials the FoundationOne CDx LOH determined through tumor singlenucleotide polymorphism (SNP) sequencing and the myChoice HRD test (Myriad Genetics) using a GI score derived from the unweighted sum of NtAI, LST, and LOH. In the first case, a tumor is considered HRD positive if %LOH is >16% and/or a BRCA1/2 mutation is detected.…”

Precision cancer medicine: Concepts, current practice, and future developments

“…Since the first reports of mutational signatures in 2012 [5], mutational signatures have been estimated through various technological platforms like whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted next-generation sequencing (NGS) panels fused with different mathematical tools (see e.g., Refs. [2,[6][7][8] for extensive reviews). For HRD detection, clinically validated assays exist (like myChoice CDx from Myriad Genetics and FoundationOne CDx from Foundation Medicine), and for MMRd, multiple algorithms suitable for NGS data have been reported (mSINGS, MSIsensor, MSIseq [9][10][11]).…”

“…[8] for extensive overview of clinical studies). HRD-positivity can be estimated/determined in several ways by large-scale genomic aberrations (telomeric allelic imbalances, LOH, and large-scale transitions), presence of SBS3, presence of an indel signature with microhomology at deletion junctions, presence of two specific SV signatures, or by classifiers like HRDetect, CHORD, and SigMA that consider all or different sets of these readouts [2,8,18]. Based on HRD prediction, it has, for instance, been shown in clinical trials that HRD-positive ovarian cancers benefitted from PARP-inhibitors, even in the absence of BRCA1/2mutations [19,20], thus establishing HRD status as a treatment-predictive factor in ovarian cancer.…”

“…The main clinical indications of HRD today are increased sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors and DSB inducing chemotherapies like platinum-based agents (see Ref. [8] for extensive overview of clinical studies). HRD-positivity can be estimated/determined in several ways by large-scale genomic aberrations (telomeric allelic imbalances, LOH, and large-scale transitions), presence of SBS3, presence of an indel signature with microhomology at deletion junctions, presence of two specific SV signatures, or by classifiers like HRDetect, CHORD, and SigMA that consider all or different sets of these readouts [2,8,18].…”