Trends in Molecular Medicine
Volume 23, Issue 12, December 2017, Pages 1121-1137
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Review
Characterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer

https://doi.org/10.1016/j.molmed.2017.10.007Get rights and content

Trends

Comprehensive molecular profiling can classify tumors according to mutational signatures which may enrich subtypes with therapeutic options.

Diagnostic tests to identify HRD phenotypes extend beyond germline and somatic mutations in BRCA1/2 and are evolving to the integration of large volumes of genomic data.

The molecular phenotype of HRD is heterogeneous, and our understanding of genetic or epigenetic aberrations in homologous recombination repair (HRR) pathways that contribute to mutagenesis remains incomplete.

Resistance mechanisms to DNA damaging agents extend beyond reversion mutations, and include indirect restoration of HRR and protection of stalled replication forks.

Combination strategies, including integration of immune-checkpoint inhibitors and trials exploring drug sequencing, may overcome resistance mechanisms.

Investigations of carcinogenesis have evolved from the identification of clonal driver mutations in candidate genes to the integration of large volumes of genomic and transcriptomic data revealing recurrently altered pathways and signatures of mutational processes. Inactivation of BRCA1, BRCA2, or PALB2 impairs efficient double-strand break repair (DSBR), giving rise to a spectrum of homologous recombination deficiency (HRD) cancer phenotypes. Harnessing HRD therapeutically has been promising in a number of tumors; these approaches include leveraging synthetic lethality by targeting alternative repair pathways via PARP inhibition, inducing HRD to modulate potential tumor vulnerabilities, and preventing mechanisms of drug resistance. It is therefore crucial to develop assays for accurate HRD detection and to broaden the patient population who can avail of novel treatment options.

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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