Development of a Genomic Signatures-Based Predictor of Initial Platinum-Resistance in Advanced High-Grade Serous Ovarian Cancer Patients

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

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Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

Cancers ◽

10.3390/cancers12020279 ◽

2020 ◽

Vol 12 (2) ◽

pp. 279

Author(s):

Stefan Poschner ◽

Judith Wackerlig ◽

Dan Cacsire Castillo-Tong ◽

Andrea Wolf ◽

Isabel von der Decken ◽

...

Keyword(s):

Ovarian Cancer ◽

High Resolution Mass Spectrometry ◽

Estrogen Metabolism ◽

Ovarian Cancer Cells ◽

Platinum Resistance ◽

High Grade ◽

Serous Ovarian Cancer ◽

Platinum Sensitive ◽

Platinum Based Chemotherapy ◽

The Impact

High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to “platinum-sensitive”, exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.

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Prognostic Value of TNFR2 and STAT3 among High-Grade Serous Ovarian Cancer Survivors According to Platinum Sensitivity

Diagnostics ◽

10.3390/diagnostics11030526 ◽

2021 ◽

Vol 11 (3) ◽

pp. 526

Author(s):

Janisha Silva Raju ◽

Nor Haslinda Abd. Aziz ◽

Ghofraan Abdulsalam Atallah ◽

Chew Kah Teik ◽

Mohamad Nasir Shafiee ◽

...

Keyword(s):

Ovarian Cancer ◽

Protein Expression ◽

Ovarian Tissue ◽

Progression Free Survival ◽

High Grade ◽

Serous Ovarian Cancer ◽

Free Survival ◽

Platinum Sensitive ◽

Platinum Based Chemotherapy ◽

Survival Interval

This study’s goal was to determine the protein expression level of tumour necrosis factor receptor 2 (TNFR2) and signal transducer and activator of transcription 3 (STAT3) in high-grade serous ovarian cancer (HGSC) tissues in relation to the platinum-based chemotherapy response and the prognosis outcome. A total of 25 HGSC patients underwent primary surgical debulking followed by first-line adjuvant platinum-based chemotherapy. Tissue microarray (TMA) slides were constructed utilising archived formalin fixed paraffin embedded (FFPE). The protein expression of TNFR2 and STAT3 were analysed using immunohistochemistry (IHC) staining and subsequently were correlated to the clinicopathological characteristics, platinum sensitivity as well as the duration of progression-free survival. About 14 out of 25 patients (56.0%) were platinum-sensitive. The progression free survival was significantly longer in the platinum-sensitive (PS) group when compared to those with the platinum-resistant group (PR), p = 0.0001. Among patients with TNFR2 strong expression on ovarian tissue, there was a significantly longer progression-free survival interval of 540 days in the PS group compared to PR, p = 0.0001. Patients with STAT3 expression also showed significantly better progression-free survival of 660 days in the PS group when compared to the PR group, p = 0.0001. In conclusion, patients with strong TNFR2 and STAT3 expression in the ovarian tissue had significantly longer progression-free survival interval in the PS group. Nevertheless, further research with a larger number of tissues may be required to demonstrate further significant differences.

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Promoter Methylation of the MGRN1 Gene Predicts Prognosis and Response to Chemotherapy of High-Grade Serous Ovarian Cancer Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.659254 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiao-fei Li ◽

Hai-yan Sun ◽

Tian Hua ◽

Hai-bo Zhang ◽

Yun-jie Tian ◽

...

Keyword(s):

Ovarian Cancer ◽

Mrna Expression ◽

Promoter Region ◽

Upstream Region ◽

Platinum Resistance ◽

High Grade ◽

Serous Ovarian Cancer ◽

Kaplan Meier ◽

Response To Chemotherapy ◽

Low Expression

Aberrant DNA methylation is considered to play a critical role in the chemoresistance of epithelial ovarian cancer (EOC). In this study, we explored the relationship between hypermethylation of the Mahogunin Ring Finger 1 (MGRN1) gene promoter and primary chemoresistance and clinical outcomes in high-grade serous ovarian cancer (HGSOC) patients. The MALDI-TOF mass spectrometry assays revealed a strong association between hypermethylation of the MGRN1 upstream region and platinum resistance in HGSOC patients. Spearman’s correlation analysis revealed a significantly negative connection between the methylation level of MGRN1 and its expression in HGSOC. In vitro analysis demonstrated that knockdown of MGRN1 reduced the sensitivity of cells to cisplatin and that expression of EGR1 was significantly decreased in SKOV3 cells with low levels of MGRN1 expression. Similarly, EGR1 mRNA expression was lower in platinum-resistant HGSOC patients and was positively correlated with MGRN1 mRNA expression. Kaplan-Meier analyses showed that high methylation of the MGRN1 promoter region and low expression of MGRN1 were associated with worse survival of HGSOC patients. In multivariable models, low MGRN1 expression was an independent factor predicting poor outcome. Furthermore, low expression of EGR1 was also been confirmed to be significantly related to the poor prognosis of HGSOC patients by Kaplan-Meier. The hypermethylation of the MGRN1 promoter region and low expression of MGRN1 were associated with platinum resistance and poor outcomes in HGSOC patients, probably by altering EGR1 expression.

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Evolution of platinum resistance in high-grade serous ovarian cancer

The Lancet Oncology ◽

10.1016/s1470-2045(11)70123-1 ◽

2011 ◽

Vol 12 (12) ◽

pp. 1169-1174 ◽

Cited By ~ 108

Author(s):

Susanna L Cooke ◽

James D Brenton

Keyword(s):

Ovarian Cancer ◽

Platinum Resistance ◽

High Grade ◽

Serous Ovarian Cancer

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Role of discoidin domain receptor 2 (DDR2) and microRNA-182 in survival of women with high-grade serous ovarian cancer

Tumor Biology ◽

10.1177/1010428318823988 ◽

2019 ◽

Vol 41 (1) ◽

pp. 101042831882398

Author(s):

Susana Ramalho ◽

Liliana AL De Angelo Andrade ◽

Cássio Cardoso Filho ◽

Rodrigo de Andrade Natal ◽

Marina Pavanello ◽

...

Keyword(s):

Ovarian Cancer ◽

Residual Disease ◽

Figo Stage ◽

Stage I ◽

High Grade ◽

Serous Ovarian Cancer ◽

Discoidin Domain Receptor ◽

Post Surgery ◽

Platinum Based Chemotherapy ◽

Discoidin Domain Receptor 2

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II – versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II – versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p < 0.001). In this relatively large cohort of women with HSGOC, higher DDR2 expression was associated with lower miR-182 levels and worse PFS, suggesting that these molecules may be associated with mechanisms of HGSOC progression.

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