Systematic Analysis of Homologous Recombination Deficiency Testing in Ovarian Cancer—Development of Recommendations for Optimal Assay Performance

Romey, Marcel; Rodepeter, Fiona; Hattesohl, Akira; Kaiser, Kristin; Teply-Szymanski, Julia; Heitz, Florian; Staebler, Annette; Serra, Violeta; Grass, Albert; Marmé, Frederik; Timms, Kirsten M.; Harter, Philipp; Llop-Guevara, Alba; Kommoss, Stefan; Boekhoff, Jelena; Denkert, Carsten

doi:10.1016/j.modpat.2024.100445

Cited by 2 publications

References 33 publications

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Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation

Coulson-Gilmer,

Littler,

Barnes

et al. 2024

NAR Cancer

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A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of TIMELESS, a replisome accelerator. However, the nature of the vulnerability responsible for intrinsic sensitivity remains undetermined. To understand PARG activity dependency, we analysed Timeless model systems and intrinsically sensitive ovarian cancer cells. We show that nucleoside supplementation rescues all phenotypes associated with PARG inhibitor sensitivity, including replisome speed and fork stalling, S-phase completion and mitotic entry, proliferation dynamics and clonogenic potential. Importantly nucleoside supplementation restores PARG inhibitor resistance despite the continued presence of PAR chains, indicating that sensitivity does not correlate with PAR levels. In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances.

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Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation

Coulson-Gilmer,

Littler,

Barnes

et al. 2024

NAR Cancer

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Combination ofBRCAdeep targeted sequencing and shallow whole genome sequencing to detect homologous recombination deficiency in ovarian cancer

Nguyen,

Tran,

Nguyen

et al. 2024

Preprint

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BackgroundsAssessing homologous recombination deficiency (HRD) has been recommended by clinical guidelines for patients with ovarian cancer (OC) as it predicts sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). However, HRD testing is complex and either inaccessible or unaffordable for majority of OC patients in developing countries. Consequently, the prevalence of HRD in OC remains unknown.MethodsWe examined HRD status of 77 Vietnamese patients with OC using a new laboratory-developed test (HRD Insight, Gene Solutions). Tumor DNA was extracted from FFPE samples, followed by next-generation sequencing to detect deleterious or suspected deleterious variants inBRCA1/2genes. Shallow whole genome sequencing was performed to determine the whole Genomic Instability (wGI) score by assessing the presence of large-scale intra-chromosomal copy number alterations.ResultsThe assay was first benchmarked against commercial HRD kits including TruSight Oncology 500 HRD (Illumina), SOPHiA DDM HRD Solutions (Sophia Genetics) and HRD Focus Panel (AmoyDx), and showed an overall percent agreement of 90.0%, 96.3%, and 96.4% respectively. The successful rate of sequencing was 94.8% (73/77) and the prevalence of HRD in OC patients was 54.8% (40/73).BRCAmutations and positive wGI scores were found in 16.4% (12/73) and 47.9% (35/73) of the patients respectively. Among those with wild-typeBRCA1/2, 40.5% of them had positive wGI scores and hence positive HRD. Age at diagnosis was not affected by bothBRCAand wGI status.ConclusionsHRD Insight assay could accurately and robustly determine the HRD status of ovarian tissue samples, including those with low quality.

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Systematic Analysis of Homologous Recombination Deficiency Testing in Ovarian Cancer—Development of Recommendations for Optimal Assay Performance

Cited by 2 publications

References 33 publications

Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation

Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation

Combination ofBRCAdeep targeted sequencing and shallow whole genome sequencing to detect homologous recombination deficiency in ovarian cancer

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