Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

Mangogna, Alessandro; Munari, Giada; Pepe, Francesco; Maffii, Edoardo; Giampaolino, Pierluigi; Ricci, Giuseppe; Fassan, Matteo; Malapelle, Umberto; Biffi, Stefania

doi:10.3390/jpm13020284

Cited by 17 publications

(6 citation statements)

References 81 publications

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“…Many comparative studies between commercially available assay and Myriad MyChoice have been made, but often clinical assessment is lacking [ 40 ]. This is particularly important given the intricate nature of HRD assays and the need for them to be thoroughly evaluated to ensure their efficacy in a clinical setting, also reviewed in [ 31 , 41 ]. The ENGOT HRD initiative that made samples of the ENGOT PAOLA-1 study available for assay validation has proven to be an invaluable resource to the scientific community, as it has facilitated the validation of several HRD assays, thereby paving the way for more precise and personalized treatment approaches.…”

Section: Discussionmentioning

confidence: 99%

Development of the NOGGO GIS v1 Assay, a Comprehensive Hybrid-Capture-Based NGS Assay for Therapeutic Stratification of Homologous Repair Deficiency Driven Tumors and Clinical Validation

Willing

Vollbrecht

Vössing

et al. 2023

Cancers

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The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution’s specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25–85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The “NOGGO GIS v1 assay” performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.

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Section: Discussionmentioning

confidence: 99%

Development of the NOGGO GIS v1 Assay, a Comprehensive Hybrid-Capture-Based NGS Assay for Therapeutic Stratification of Homologous Repair Deficiency Driven Tumors and Clinical Validation

Willing

Vollbrecht

Vössing

et al. 2023

Cancers

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“…In fact, beyond their known role in double-strand DNA break repair pathways and in particular in the regulation of HR, these mutations also have other functions such as being a regulator of oxidative stress and cell cycle progression (BRCA1) or being involved in transcriptional regulation (BRCA1/2) [25,26]. In this context, starting from the main function of these genes, researchers have increasingly emphasized the analysis of the link between their dysregulation and tumorigenesis and consequently the study of homologous recombination repair (HRR) deficiencies which has led to significant therapeutic advancements on urogenital cancers [26][27][28]. Moreover, the observed heterogeneity in ovarian tumor cells, including variations in the tumor microenvironment and metabolic pathways, offers a deeper understanding of tumorigenesis.…”

Section: Urogenital Cancers: Insights From Ovarian and Prostate Tumor...mentioning

confidence: 99%

Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients

De Lazzari,

Opattova,

Arena

2024

J Exp Clin Cancer Res

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Over the last few decades, the incidence of urogenital cancers has exhibited diverse trends influenced by screening programs and geographical variations. Among women, there has been a consistent or even increased occurrence of endometrial and ovarian cancers; conversely, prostate cancer remains one of the most diagnosed malignancies, with a rise in reported cases, partly due to enhanced and improved screening efforts.Simultaneously, the landscape of cancer therapeutics has undergone a remarkable evolution, encompassing the introduction of targeted therapies and significant advancements in traditional chemotherapy. Modern targeted treatments aim to selectively address the molecular aberrations driving cancer, minimizing adverse effects on normal cells. However, traditional chemotherapy retains its crucial role, offering a broad-spectrum approach that, despite its wider range of side effects, remains indispensable in the treatment of various cancers, often working synergistically with targeted therapies to enhance overall efficacy.For urogenital cancers, especially ovarian and prostate cancers, DNA damage response inhibitors, such as PARP inhibitors, have emerged as promising therapeutic avenues. In BRCA-mutated ovarian cancer, PARP inhibitors like olaparib and niraparib have demonstrated efficacy, leading to their approval for specific indications. Similarly, patients with DNA damage response mutations have shown sensitivity to these agents in prostate cancer, heralding a new frontier in disease management. Furthermore, the progression of ovarian and prostate cancer is intricately linked to hormonal regulation. Ovarian cancer development has also been associated with prolonged exposure to estrogen, while testosterone and its metabolite dihydrotestosterone, can fuel the growth of prostate cancer cells. Thus, understanding the interplay between hormones, DNA damage and repair mechanisms can hold promise for exploring novel targeted therapies for ovarian and prostate tumors.In addition, it is of primary importance the use of preclinical models that mirror as close as possible the biological and genetic features of patients’ tumors in order to effectively translate novel therapeutic findings “from the bench to the bedside”.In summary, the complex landscape of urogenital cancers underscores the need for innovative approaches. Targeted therapy tailored to DNA repair mechanisms and hormone regulation might offer promising avenues for improving the management and outcomes for patients affected by ovarian and prostate cancers.

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“…These observations suggest that MAGI1-low MCF7 cells may have a deficient DNA damage response and repair activity. HRD refers to the inability to efficiently repair DNA DSBs using the HR repair pathway [81]. In addition, inactivation or defects in DNA repair genes as well as cells with a reduced ability to undergo apoptosis in response to DNA damage tend to accumulate mutations [82].…”

Section: Transcriptome Analyses Revealed Biologicalmentioning

confidence: 99%

MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER+ Breast Cancer

Wörthmüller,

Disler,

Pradervand

et al. 2023

Cells

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MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer (BC), and its loss correlates with a more aggressive phenotype. To identify the pathways and events affected by MAGI1 loss, we deleted the MAGI1 gene in the ER+ MCF7 BC cell line and performed RNA sequencing and functional experiments in vitro. Transcriptome analyses revealed gene sets and biological processes related to estrogen signaling, the cell cycle, and DNA damage responses affected by MAGI1 loss. Upon exposure to TNF-α/IFN-γ, MCF7 MAGI1 KO cells entered a deeper level of quiescence/senescence compared with MCF7 control cells and activated the AKT and MAPK signaling pathways. MCF7 MAGI1 KO cells exposed to ionizing radiations or cisplatin had reduced expression of DNA repair proteins and showed increased sensitivity towards PARP1 inhibition using olaparib. Treatment with PI3K and AKT inhibitors (alpelisib and MK-2206) restored the expression of DNA repair proteins and sensitized cells to fulvestrant. An analysis of human BC patients’ transcriptomic data revealed that patients with low MAGI1 levels had a higher tumor mutational burden and homologous recombination deficiency. Moreover, MAGI1 expression levels negatively correlated with PI3K/AKT and MAPK signaling, which confirmed our in vitro observations. Pharmacological and genomic evidence indicate HDACs as regulators of MAGI1 expression. Our findings provide a new view on MAGI1 function in cancer and identify potential treatment options to improve the management of ER+ BC patients with low MAGI1 levels.

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Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

Cited by 17 publications

References 81 publications

Development of the NOGGO GIS v1 Assay, a Comprehensive Hybrid-Capture-Based NGS Assay for Therapeutic Stratification of Homologous Repair Deficiency Driven Tumors and Clinical Validation

Development of the NOGGO GIS v1 Assay, a Comprehensive Hybrid-Capture-Based NGS Assay for Therapeutic Stratification of Homologous Repair Deficiency Driven Tumors and Clinical Validation

Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients

MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER+ Breast Cancer

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