Prediction of Platinum-based Chemotherapy Response in Advanced High-grade Serous Ovarian Cancer: ADC Histogram Analysis of Primary Tumors

2020 ◽  
Author(s):  
Jing Lu ◽  
Hai Ming Li ◽  
Song Qi Cai ◽  
Shu Hui Zhao ◽  
Feng Hua Ma ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Histogram Analysis ◽  
Chemotherapy Response ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Platinum Based Chemotherapy

scholarly journals Prognostic Significance of SLFN11 Methylation in Plasma Cell-Free DNA in Advanced High-Grade Serous Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 4
Author(s):  
Victoria Tserpeli ◽  
Dimitra Stergiopoulou ◽  
Dora Londra ◽  
Lydia Giannopoulou ◽  
Paul Buderath ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Methylation ◽  
Liquid Biopsy ◽  
Methylation Status ◽  
Prognostic Significance ◽  
Gene Promoters ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Platinum Based Chemotherapy

Background: Epigenetic alterations in ctDNA are highly promising as a source of novel potential liquid biopsy biomarkers and comprise a very promising liquid biopsy approach in ovarian cancer, for early diagnosis, prognosis and response to treatment. Methods: In the present study, we examined the methylation status of six gene promoters (BRCA1, CST6, MGMT, RASSF10, SLFN11 and USP44) in high-grade serous ovarian cancer (HGSOC). We evaluated the prognostic significance of DNA methylation of these six gene promoters in primary tumors (FFPEs) and plasma cfDNA samples from patients with early, advanced and metastatic HGSOC. Results: We report for the first time that the DNA methylation of SLFN11 in plasma cfDNA was significantly correlated with worse PFS (p = 0.045) in advanced stage HGSOC. Conclusions: Our results strongly indicate that SLFN11 epigenetic inactivation could be a predictor of resistance to platinum drugs in ovarian cancer. Our results should be further validated in studies based on a larger cohort of patients, in order to further explore whether the DNA methylation of SLFN11 promoter could serve as a potential prognostic DNA methylation biomarker and a predictor of resistance to platinum-based chemotherapy in ovarian cancer.

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

2021 ◽  
Vol 10 ◽  
Author(s):  
Yuan Li ◽  
Xiaolan Zhang ◽  
Yan Gao ◽  
Chunliang Shang ◽  
Bo Yu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Predictive Accuracy ◽  
Predictive Performance ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Single Nucleotide Variants ◽  
Tissue Samples ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy

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.

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

Tumor Biology ◽  
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.

scholarly journals Is BRCA mutational status a predictor of platinum-based chemotherapy related hematologic toxicity in high-grade serous ovarian cancer patients?

2019 ◽  
Vol 154 (1) ◽  
pp. 138-143 ◽  
Author(s):  
Federica Tomao ◽  
Lucia Musacchio ◽  
Federica Di Mauro ◽  
Serena Maria Boccia ◽  
Violante Di Donato ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Hematologic Toxicity ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Mutational Status ◽  
Platinum Based Chemotherapy

Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13580-e13580
Author(s):  
Renata Duchnowska ◽  
Anna Maria Supernat ◽  
Rafał Pęksa ◽  
Marta Łukasiewicz ◽  
Tomasz Stokowy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Somatic Mutations ◽  
Dna Damage Repair ◽  
Genetic Alterations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Damage Repair

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.

scholarly journals Somatic Mutations in BRCA2 BRC Repeat Associated with Outcome in Patients with High Grade Serous Ovarian Cancer

2020 ◽  
Author(s):  
Guonan Zhang ◽  
Jie Zhang ◽  
Yi Zhu ◽  
Hong Liu ◽  
Yu Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Progression Free Survival ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Blood Leukocytes ◽  
Free Survival ◽  
Chemotherapy Sensitivity ◽  
Factors Affecting ◽  
Platinum Based Chemotherapy

Abstract BackgroundThe interaction between BRCA2 BRC repeats and RAD51 is one of the great important factors affecting the homologous recombination in DNA damage repair of tumor cells. We investigated the effect of BRCA2 BRC repeat mutations on outcome in patients with high grade serous ovarian cancer (HGSOC) who received platinum-based chemotherapy.MethodsWe identified the type and location of BRCA2 BRC repeat mutations by PCR and DNA sequencing in tumor and peripheral blood leukocytes (PBL) samples of 113 patients with stage IIIC/IV high grade serous ovarian cancer (HGSOC), and assessed chemotherapy-free interval (CFI), progression-free survival (PFS) and overall survival (OS).Results24 (21.23%) cases with somatic mutation were identified in 113 HGSOC patients. Among them, 8 (7.1%) cases with nonsense mutation resulting in BRCA2 truncation significantly prolonged median CFI (37 vs 8 months,P=0.000), PFS (43 vs 14 months, p=0.000) and OS (56 vs 31 months, P=0.002); Interestingly, 16 (14.13%) cases with missense mutation also prolonged median CFI (15 vs 8 months, P=0.044), PFS (21 vs 14 months, P=0.049) and OS ( 38 vs 31 months, P=0.037). ConclusionsSomatic mutations in BRCA2 BRC5-8 repeat motifs are associated with platinum-based chemotherapy sensitivity and a better outcome in patients with HGSOC.

scholarly journals Odd-skipped related 2 (OSR2) is differentially expressed in high-grade serous ovarian cancers.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Cell Fate ◽  
Microarray Data ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Differentially Expressed ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Ovarian Cancers

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of normal ovary with that of primary tumors from women diagnosed with HGSC using published microarray data (2,3). We previously identified forkhead box L2 (4), (FOXL2) as among the genes whose expression was most different in HGSC ovarian tumors when compared to the ovary. Here, we find that potential FOXL2 transcriptional target (5,6) odd-skipped related gene OSR2 (7) is differentially expressed in high-grade serous ovarian cancer, and could be observed in independent tumor microarray data (2,3). These data reveal perturbed expression of a target gene of a key transcription factor and specifier of ovarian cell fate in high-grade serous ovarian cancers.

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