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Characterisation of homologous recombination deficiency in paired primary and recurrent high-grade serous ovarian cancer.

ABSTRACT: BACKGROUND:Homologous recombination deficiency (HRD) is shown to predict response to DNA-damaging therapies in patients with high-grade serous ovarian cancer (HGSOC); however, changes in HRD during progression remains unknown. METHODS:HRD scores were evaluated in paired primary and/or recurrent HGSOC samples (N?=?107) from 54 patients with adjuvant platinum-based chemotherapy. BRCA1/2 mutation, BRCA1 methylation, loss of heterozygosity (LOH), and HRD scores were characterised using tumour DNA-based next-generation sequencing assays. RESULTS:Among 50 evaluable pairs (N?=?100 samples), high intra-patient correlation in HRD score was observed (r2?=?0.93). BRCA1/2 mutations, BRCA1/2 LOH, and HRD were maintained between primary and recurrent samples, except for one pair in which a BRCA1 reversion mutation was identified in the recurrent sample. Despite the reversion, both samples were classified as having high HRD scores (???42). All samples with BRCA1/2 mutations exhibited high HRD scores; however, high HRD scores were more prevalent than BRCA1/2 mutations (55% vs. 30%, respectively). CONCLUSION:Markers of HRD were maintained between the primary and recurrent samples, regardless of other genomic changes that occurred during recurrence. HRD score/markers in primary tumours may be valuable and adequate for selection of platinum-based therapy and/or poly-ADP-ribose-polymerase (PARP) inhibitors in recurrent HGSOC.

SUBMITTER: Patel JN

PROVIDER: S-EPMC6219476 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Characterisation of homologous recombination deficiency in paired primary and recurrent high-grade serous ovarian cancer.

Patel Jai N JN Braicu Ioana I Timms Kirsten M KM Solimeno Cara C Tshiaba Placede P Reid Julia J Lanchbury Jerry S JS Darb-Esfahani Silvia S Ganapathi Mahrukh K MK Sehouli Jalid J Ganapathi Ram N RN

British journal of cancer 20181015 9

<h4>Background</h4>Homologous recombination deficiency (HRD) is shown to predict response to DNA-damaging therapies in patients with high-grade serous ovarian cancer (HGSOC); however, changes in HRD during progression remains unknown.<h4>Methods</h4>HRD scores were evaluated in paired primary and/or recurrent HGSOC samples (N = 107) from 54 patients with adjuvant platinum-based chemotherapy. BRCA1/2 mutation, BRCA1 methylation, loss of heterozygosity (LOH), and HRD scores were characterised usin ...[more]

PMID: 30318511

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Project description:Background: The homologous recombination (HR) pathway defects in cancers induced abrogation of cell cycle checkpoints, resulting in the accumulation of DNA damage, mitotic catastrophe, and cell death. Cancers with BRCA1/2 loss and other accumulation of similar genomic scars resulting in HRD displayed increased sensitivity to chemotherapy. Our study aimed to explore HRD score genetic mechanisms and subsequent clinical outcomes in human cancers, especially ovarian cancer. Methods: We analyzed TCGA data of HRD score in 33 cancer types and evaluated HRD score distribution and difference among tumor stages and between primary and recurrent tumor tissues. A weighted gene co-expression network analysis (WGCNA) was performed to identify highly correlated genes representing essential modules contributing to the HRD score and distinguish the hub genes and significant pathways. We verified HRD status predicting roles in patients' overall survival (OS) with univariate and multivariate Cox regression analyses and built the predicting model for patient survival. Results: We found that the HRD score increased with the rise in tumor stage, except for stage IV. The HRD score tended to grow up higher in recurrent tumor tissue than in their primary counterparts (p = 0.083). We constructed 15 co-expression modules with WGCNA, identified co-expressed genes and pathways impacting the HRD score, and concluded that the HRD score was tightly associated with tumor cells replication and proliferation. A combined HRD score ≥42 was associated with shorter OS in 33 cancer types (HR = 1.010, 95% CI: 1.008-1.011, p < 0.001). However, in ovarian cancer, which ranked the highest HRD score among other cancers, HRD ≥42 cohort was significantly associated with longer OS (HR = 0.99, 95% CI: 0.98-0.99, p < 0.0001). We also built a predicting model for 3 and 5 years survival in HGSC patients. Conclusion: A quantitative HRD score representing the accumulated genomic scars was dynamically increasing in proliferating tumor cells since the HRD score was tightly correlated to tumor cell division and replication. We highlighted HRD score biomarker role in prognosis prediction of ovarian cancer.

Project description:BackgroundsOvarian cancer (OC) is still the leading aggressive and lethal disease of gynecological cancers, and platinum-based regimes are the standard treatments. However, nearly 20%-30% of patients with OC are initial platinum resistant (IPR), and there is a lack of valid tools to predict whether they will be primary platinum resistant or not prior to chemotherapy.MethodsTranscriptome data from The Cancer Genome Atlas (TCGA) was downloaded as the training data, and transcriptome data of GSE15622, GSE102073, GSE19829, and GSE26712 were retrieved from Gene Expression Omnibus (GEO) as the validation cohorts. Differentially expressed genes (DEGs) were selected between platinum-sensitive and platinum-resistant patients from the training cohort, and multiple machine-learning algorithms [including random forest, XGboost, and least absolute shrinkage and selection operator (LASSO) regression] were utilized to determine the candidate genes from DEGs. Then, we applied logistic regression to establish the IPR signature based on the expression. Finally, comprehensive clinical, genomic, and survival feature were analyzed to understand the application value of the established IPR signature.ResultsA total of 532 DEGs were identified between platinum-resistant and platinum-sensitive samples, and 11 of them were shared by these three-machine learning algorithms and utilized to construct an IPR prediction signature. The area under receiver operating characteristic curve (AUC) was 0.841 and 0.796 in the training and validation cohorts, respectively. Notably, the prediction capacity of this signature was stable and robust regardless of the patients' homologous recombination deficiency (HRD) and mutation burden status. Meanwhile, the genomic feature was concordant between samples with high- or low-IPR signature, except a significantly higher prevalence of gain at Chr19q.12 (regions including CCNE1) in the high-IPR signature samples. The efficacy of prediction of platinum resistance of IPR signature successfully transferred to the precise survival prediction, with the AUC of 0.71, 0.72, and 0.66 to predict 1-, 3-, and 5-year survival, respectively. At last, we found a significantly different tumor-infiltrated lymphocytes feature, including lower abundance of CD4+ naive T cells in the samples with high-IPR signature. A relatively lower tumor immune dysfunction and exclusion (TIDE) value and more sensitivity to multiple therapies including Gefitinib may suggest the potency to transfer from platinum-based therapy to immunotherapy or target therapies in patients with high-IPR signature.ConclusionOur study established an IPR signature based on the expression of 11 genes that could stably and robustly distinguish OC patients with IPR and/or poor outcomes, which may guide therapeutic regimes tailoring.

Project description:BackgroundHigh-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs.Experimental designWe tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo.ResultsWe show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts.ConclusionOur findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

Dataset Information

Characterisation of homologous recombination deficiency in paired primary and recurrent high-grade serous ovarian cancer.

Publications

Characterisation of homologous recombination deficiency in paired primary and recurrent high-grade serous ovarian cancer.

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