Trends in Molecular Medicine
ReviewCharacterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer
Section snippets
Friend and Foe: The Double-Edged Sword of HRD
Crucial to cell viability, genomic integrity is maintained by the complex network of the DNA damage response (DDR; see Glossary) which includes cell-cycle checkpoints and DNA repair pathways activated by endogenous and exogenous cell stressors such as reactive oxygen species (ROS) and cytotoxic agents. In response to DNA damage these processes either activate repair pathways or commit a cell to apoptosis or senescence. Dysregulation of this highly organized network can predispose to malignancy,
DNA DSBs and HRR
DNA damage occurs in many forms including single-strand breaks (SSBs), base modifications, and DSBs. SSBs are prevalent and arise from DNA damage induced by ROS and also indirectly from base excision repair (BER) of damaged bases or from intermediates emerging from erroneous DNA topoisomerase 1 activity [1]. In mammalian cells, SSBs quickly bind the enzyme PARP1, ensuring efficient repair (see below) [2]. The number of directly introduced DSBs in healthy mammalian cells is low, as determined by
Genetic Aberrations Associated with HRD
HRD can arise from germline and/or somatic inactivation of HRR pathway genes. In humans, germline mutations in BRCA1, BRCA2, and PALB2 are associated with the hereditary breast and ovarian cancer syndromes which predispose heterozygous carriers to breast, ovarian, prostate, and pancreatic ductal adenocarcinoma (PDAC) [6]. Mutations in BRCA1/2 confer a 40–80% lifetime risk of developing breast cancer (BC) and a 11–40% risk of epithelial ovarian cancer (EOC) [7]. The absolute risk of BC in
Frequency and Characterization of HRD Molecular Phenotypes across Human Malignancies
Frequencies of HRD phenotypes vary according to both tumor type and the assays used to interrogate them. In The Cancer Genome Atlas (TCGA) characterization of high-grade serous ovarian cancers by exome sequencing (n = 316) and gene expression analysis (microarrays, n = 489), germline and/or somatic mutations in BRCA1/2 were present in 22% of cases, and a further 11% lost BRCA1 expression through DNA hypermethylation [9]. Up to 50% of ovarian tumors displayed disruptions of genes in the HRR pathway
Development of HRD Diagnostic Assays for Human Cancers
The characterization of HRD will continue to improve as the number of sequenced tumors increases, but does not provide a readily translatable assay for clinical use (Table 1). BRACAnalysis™ CDx (Myriad) and FoundationFocus™ CDxBRCA are both FDA approved assays for the detection of germline BRCA mutations, and the latter is also approved for the detection of somatic mutations. Both are companion diagnostics that are used to predict PARPi response and therapeutic agents which can specifically
HRD Phenotype and the Development of Effective Therapeutics
Because HRD occurs in an appreciable fraction of malignancies, it is appealing to study as a prognostic and predictive marker. Moreover, HRD tumors are paradoxically vulnerable, relying on alternative pathways for DNA repair that might be therapeutically targeted. Both platinum-based regimens and PARPi have demonstrated sensitivity for HRD-associated tumors.
BRCA1/2-mutated ovarian cancers have an improved prognosis that is perhaps secondary, at least in part, to superior treatment responses 10,
Resistance and Restoration of HRR
Resistance to PARPi is increasingly being characterized at the genomic level. For instance, acquired reversion mutations in BRCA1 and BRCA2 have been shown in patient tumor samples to restore the open reading frame (ORF), reinstating functional protein translation and allowing DNA repair 75, 76. This has emerged as a possible cause for both platinum and PARPi resistance in ovarian cancer patients with germline BRCA1/2 mutations, which emphasizes the importance of combining these agents
Concluding Remarks
The HRD phenotype is increasingly found in multiple malignancies and poses an exciting candidate therapeutic target for DNA damaging agents in combination therapies. Furthermore, downregulation of efficient HRR may be induced by systemic therapies, providing a targeted approach in patients with HRD-proficient malignancies. Immunogenicity of HRD-associated malignancies and the immunomodulatory effects of PARP inhibition may be harnessed in combination approaches to treat HRD cancers. A specific
Acknowledgments
This work was supported by the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario and a charitable donation from the Canadian Friends of the Hebrew University (Alex U. Soyka), and by a Canadian Cancer Society Research Institute grant (702316) to S.G.
Glossary
- Alternative end-joining (alt-EJ) pathways
- in addition to the classical NHEJ pathway, alt-EJ pathways represent a poorly defined auxiliary pathway and associate with nucleotide end-joining using microhomology (>4 bp) before ligation.
- Apoptosis
- a complex, genetically regulated process leading to cellular self-destruction that is triggered by a variety of stimuli including DNA damage.
- ARIEL2 study
- a Phase II study of rucaparib in patients with relapsed platinum-sensitive high-grade ovarian cancer and a
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Cited by (40)
Patient Assessment and Therapy Planning Based on Homologous Recombination Repair Deficiency
2023, Genomics, Proteomics and BioinformaticsA phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium
2022, Gynecologic OncologyCitation Excerpt :One of the most commonly mutated genes in endometrial cancer is phosphatase and tensin homolog (PTEN) [15]. Loss of function of PTEN or AT-rich interactive domain-containing protein 1A (ARID1A), another commonly mutated gene, leads to decreased DNA damage repair capabilities similar to the BRCA driven HRD phenotype [16–18]. While the majority of endometrial tumors tested demonstrating an HRD phenotype appear to be non-endometrioid [19] in endometrial cancers, PTEN loss of function was frequently observed in all TCGA subgroups except copy number high, with an overall incidence of approximately 57% [20].
Tackling PARP inhibitor resistance
2021, Trends in CancerCitation Excerpt :Recent studies have shown promising therapeutic responses in genetically HR-proficient cancers that have acquired HRD status through epigenetic silencing of HR genes, such as by BRCA1 promoter hypermethylation [6]. The phenotypic outcome of impaired BRCA or HR function, termed ‘BRCA-ness,’ gives rise to a specific mutational signature that can be used to stratify patients who might benefit from PARPi therapy [7]. Using new diagnostic tools for detection of HRD in cancers, up to 50% of ovarian carcinomas [6] and 69% of triple-negative breast cancers [8,9] were found to exhibit HRD and might therefore benefit from PARPi therapy.
Identification of miR-210 and combination biomarkers as useful agents in early screening non-small cell lung cancer
2020, GeneCitation Excerpt :The homologous recombination pathway has been identified as an error-free DNA-repair system and can be activated when double-strand damage induced by ultraviolet light, spontaneous mutations, or some chemotherapies. The abnormal activation of homologous recombination pathway may result in physiological alterations towards carcinogenesis (O'Kane et al., 2017). The mismatch repair pathway exerts a critical part in recognizing and correcting DNA biosynthetic errors which result from inaccurate nucleotide incorporation during the process of replication.