scholarly journals ZNF76 predicts prognosis and response to platinum chemotherapy in human ovarian cancer

2021 ◽  
Author(s):  
Tian Hua ◽  
Rui-min Wang ◽  
Xiao-chong Zhang ◽  
Bei-bei Zhao ◽  
Shao-bei Fan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Strong Relationship ◽  
Platinum Resistance ◽  
Cox Regression Analysis ◽  
Platinum Based Chemotherapy ◽  
Low Expression

Ovarian cancer (OV) is the most lethal gynecologic malignancy. One major reason of the high mortality of the disease is due to platinum-based chemotherapy resistance. Increasing evidence reveals the important biological functions and clinical significance of zinc finger proteins (ZNFs) in OV. In this study, the relationship between zinc finger protein 76 (ZNF76) and clinical outcome and platinum resistance in patients with OV was explored. We further analyzed ZNF76 expression via multiple gene expression databases and identified its functional networks using cBioPortal. RT-qPCR and IHC assay shown that the ZNF76 mRNA and protein expression were significantly lower in OV tumor than that in normal ovary tissues. A strong relationship between ZNF76 expression and platinum resistance was determined in patients with OV. The low expression of ZNF76 was associated with worse survival in OV. Multivariable analysis showed that the low expression of ZNF76 was an independent factor predicting poor outcome in OV. The prognosis value of ZNF76 in pan-cancer was validated from multiple cohorts using the PrognoScan database and GEPIA 2. A gene-clinical nomogram was constructed by multivariate cox regression analysis, combined with clinical characterization and ZNF76 expression in TCGA. Functional network analysis suggested that ZNF76 was involved in several biology progressions which associated with OV. Nine hub genes (CDC5L, DHX16, SNRPC, LSM2, CUL7, PFDN6, VARS, HSD17B8, and RGL2) were identified as positively associated with the expression of ZNF76 in OV. In conclusion, ZNF76 may serve as a promising prognostic-related biomarker and predict the response to platinum in OV patients.

scholarly journals Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer

2016 ◽  
Vol 397 (12) ◽  
pp. 1265-1276 ◽  
Author(s):  
Nancy Ahmed ◽  
Julia Dorn ◽  
Rudolf Napieralski ◽  
Enken Drecoll ◽  
Matthias Kotzsch ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Residual Tumor ◽  
Mrna Levels ◽  
Serous Ovarian Cancer ◽  
Cox Regression Analysis

Abstract Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO stage III/IV. A pronounced correlation between KLK6 and KLK8 mRNA expression (rs = 0.636, p < 0.001) was observed, indicating coordinate expression of both peptidases. No significant associations of clinical parameters with KLK6, KLK8, and a combined score KLK6+KLK8 were found. In univariate Cox regression analysis, elevated mRNA levels of KLK6 were significantly linked with shortened overall survival (OS) (hazard ratio [HR] = 2.07, p = 0.007). While KLK8 values were not associated with patients’ outcome, high KLK6+KLK8 values were significantly associated with shorter progression-free survival (HR = 1.82, p = 0.047) and showed a trend towards significance in the case of OS (HR = 1.82, p = 0.053). Strikingly, in multivariable analysis, elevated KLK6 mRNA values, apart from residual tumor mass, remained an independent predictive marker for poor OS (HR = 2.33, p = 0.005). As KLK6 mRNA and protein levels correlate, KLK6 may represent an attractive therapeutic target for potent and specific inhibitors of its enzymatic activity.

Plasmin(ogen) serves as a favorable biomarker for prediction of survival in advanced high-grade serous ovarian cancer

2017 ◽  
Vol 398 (7) ◽  
pp. 765-773 ◽  
Author(s):  
Shuo Zhao ◽  
Julia Dorn ◽  
Rudolf Napieralski ◽  
Axel Walch ◽  
Sandra Diersch ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Positive Staining ◽  
Mrna Levels ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Data Set ◽  
Cox Regression Analysis ◽  
Kaplan Meier

Abstract In serous ovarian cancer, the clinical relevance of tumor cell-expressed plasmin(ogen) (PLG) has not yet been evaluated. Due to its proteolytic activity, plasmin supports tumorigenesis, however, angiostatin(-like) fragments, derived from PLG, can also function as potent anti-tumorigenic factors. In the present study, we assessed PLG protein expression in 103 cases of advanced high-grade serous ovarian cancer (FIGO III/IV) by immunohistochemistry (IHC). In 70/103 cases, positive staining of tumor cells was observed. In univariate Cox regression analysis, PLG staining was positively associated with prolonged overall survival (OS) [hazard ratio (HR)=0.59, p=0.026] of the patients. In multivariable analysis, PLG, together with residual tumor mass, remained a statistically significant independent prognostic marker (HR=0.49, p=0.009). In another small patient cohort (n=29), we assessed mRNA expression levels of PLG by quantitative PCR. Here, elevated PLG mRNA levels were also significantly associated with prolonged OS of patients (Kaplan-Meier analysis; p=0.001). This finding was validated by in silico analysis of a microarray data set (n=398) from The Cancer Genome Atlas (Kaplan-Meier analysis; p=0.031). In summary, these data indicate that elevated PLG expression represents a favorable prognostic biomarker in advanced (FIGO III/IV) high-grade serous ovarian cancer.

scholarly journals Oestrogen receptor 1 mRNA is a prognostic factor in ovarian cancer patients treated with neo-adjuvant chemotherapy: determination by array and kinetic PCR in fresh tissue biopsies

2009 ◽  
Vol 16 (4) ◽  
pp. 1241-1249 ◽  
Author(s):  
Claudio Zamagni ◽  
Ralph M Wirtz ◽  
Pierandrea De Iaco ◽  
Marta Rosati ◽  
Elke Veltrup ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adjuvant Chemotherapy ◽  
Prognostic Factor ◽  
Cox Regression ◽  
Endocrine Treatment ◽  
Rank Test ◽  
Mrna Levels ◽  
Cox Regression Analysis ◽  
Platinum Based Chemotherapy ◽  
Neo Adjuvant Chemotherapy

Oestrogen receptors (ESRs) regulate the growth and differentiation of normal ovarian epithelia. However, to date their role as biomarkers in the clinical setting of ovarian cancer remains unclear. In view of potential endocrine treatment options, we tested the role of ESR1 mRNA expression in ovarian cancer in the context of a neo-adjuvant chemotherapy trial. Study participants had epithelial ovarian or peritoneal carcinoma unsuitable for optimal upfront surgery and were treated with neo-adjuvant platinum-based chemotherapy before surgery. RNA was isolated from frozen tumour biopsies before treatment. RNA expression of ESR1 was determined by microarray and reverse transcriptase kinetic PCR technologies. The prognostic value of ESR1 was tested using univariate and multivariate Cox proportional hazards models, Kaplan–Meier survival statistics and the log-rank test. ESR1 positively correlates with proliferation markers and histopathological grading. ESR1 was a significant predictor of survival as a continuous variable in the univariate Cox regression analysis. In multivariate analysis, elevated baseline ESR1 mRNA levels predicted prolonged progression-free survival (P=0.041) and overall survival (P=0.01) after neo-adjuvant chemotherapy, independently of pathological grade and age. We conclude that pretreatment ESR1 mRNA is associated with tumour growth and is a strong prognostic factor in ovarian cancer, independent of the strongest clinical parameters used in clinical routine. We suggest that ESR1 mRNA status should be considered in order to minimize possible confounding effects in ovarian cancer clinical trials, and that early treatment with anti-hormonal agents based on reliable hormone receptor status determination is worth investigating.

SLFN11 expression (exp) in castration-resistant prostate cancer (CRPC) patients (pts) to predict response to platinum-based chemotherapy (PLT).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5065-5065
Author(s):  
Vincenza Conteduca ◽  
Loredana Puca ◽  
Sheng-Yu Ku ◽  
Judy Hess ◽  
Megan Kearney ◽  
...  
Keyword(s):  
Cox Regression ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Median Number ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Cox Regression Analysis ◽  
Platinum Based Chemotherapy

5065 Background: Schlafen family member 11 (SLFN11) sensitizes tumor cells to DNA-damaging agents and has been investigated as a potential predictive biomarker of response to PLT and PARP inhibitors, especially in small cell lung cancer (Lok, CCR 2017; Pietanza, JCO 2018). We aimed to explore the predictive/prognostic role of SLFN11 in PLT-treated CRPC. Methods: We assessed tumor exp of SLFN11 in PLT-treated, metastatic CRPC pts by RNAseq (N=27) and/or CTCs (N=20) (via the Epic Sciences platform). In addition, tumor morphology for neuroendocrine (NE) features and genomic status of select genes (ie, AR, TP53, RB1, BRCA2, BRCA1, ATM) by whole exome sequencing were evaluated. Statistical comparisons used Cox regression analysis and Kaplan Meier method for the association with overall/radiographic progression free survival (OS/rPFS). A dose response curve with PLT was performed in patient-derived organoids using Cell Title Glo according to the manufacturer’s protocol. Results: 41 CRPC (including 20 CRPC-NE) treated with PLT monotherapy (N=3) or PLT combination therapy (N=38) between August 2013 and December 2017 were evaluated. Median age was 67.1 years (range 51-91). Median number of prior therapies was 2 (range 1-7). A longer median rPFS was observed in all SLFN11+ pts treated with PLT (regardless of histology, RB1, TP53, PTEN, or DNA repair status) compared to SLFN11- [5.2 vs 2.3 months, HR 3.5, 95%CI 1.6-7.7, P<0.0001]. No association was reported for OS. On multivariable analysis (Table), SLFN11 was an independent factor associated with rPFS. Organoids derived from patient tumors expressing SLFN11 showed sensitivity to PLT in vitro. Conclusions: SLFN11 exp identifies both CRPC and CRPC-NE pts with a better response to PLT. Patient-derived organoids expressing SLFN11 confirmed increased sensitivity to PLT. Larger prospective evaluation of therapy decisions based on SLFN11 exp is now required. [Table: see text]

ATL

2014 ◽  
Vol 24 (8) ◽  
pp. 1395-1400 ◽  
Author(s):  
Vilius Rudaitis ◽  
Tadas Zvirblis ◽  
Daiva Kanopiene ◽  
Dovile Janulynaite ◽  
Laimonas Griskevicius ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Cox Regression ◽  
Significant Risk ◽  
Advanced Ovarian Cancer ◽  
Advanced Stage ◽  
Wild Type ◽  
Debulking Surgery ◽  
Cox Regression Analysis ◽  
Platinum Based Chemotherapy

ObjectiveThe aim of this study was to explore BRCA mutation frequency and to evaluate its impact on prognosis of advanced-stage ovarian cancer patients treated with debulking surgery and platinum-based chemotherapy.MethodsPatients with advanced-stage epithelial ovarian cancer were enrolled in a prospective, single-center study from September 2008 to December 2011. All cases were screened for BRCA1 and BRCA2 gene mutations. Progression-free survival (PFS) was assessed between BRCA1/2 mutation carriers and BRCA1/2 wild-type patients.ResultsOne hundred seven patients were enrolled and screened for BRCA1 and BRCA2 mutations; 51.4% patients were positive for BRCA1/2 gene mutation, 63.6% of which carried a single Baltic mutation, and 98.2% of them had serous histology. Older age (hazard ratio [HR], 1.032; 95% confidence interval [CI], 1.010–1.055; P = 0.0047), nonoptimal cytoreduction (HR, 3.170; 95% CI, 1.986–5.060; P < 0.0001), and BRCA1/2 wild type (HR, 1.625 [1.003–2.632]; P = 0.0486) were significantly associated with shorter PFS in multivariate Cox regression analysis. Only the nonoptimal cytoreduction was a statistically significant risk factor for shorter overall survival (HR, 2.684; 95% CI, 1.264–5.701; P= 0.0102).ConclusionsAdvanced ovarian cancer patients harboring BRCA1/2 mutation treated with debulking surgery and platinum-based adjuvant chemotherapy have a longer PFS.

scholarly journals Hypermethylation of mismatch repair gene hMSH2 associates with platinum-resistant disease in epithelial ovarian cancer

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Hua Tian ◽  
Li Yan ◽  
Li Xiao-fei ◽  
Sun Hai-yan ◽  
Chen Juan ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ovarian Cancer ◽  
Dna Methylation ◽  
Epithelial Ovarian Cancer ◽  
Upstream Region ◽  
Platinum Resistance ◽  
Maldi Tof Mass Spectrometry ◽  
Platinum Resistant ◽  
Aberrant Dna Methylation ◽  
Low Expression

Abstract Purpose One major reason of the high mortality of epithelial ovarian cancer (EOC) is due to platinum-based chemotherapy resistance. Aberrant DNA methylation may be a potential mechanism underlying the development of platinum resistance in EOC. The purpose of this study is to discover potential aberrant DNA methylation that contributes to drug resistance. Methods By initially screening of 16 platinum-sensitive/resistant samples from EOC patients with reduced representation bisulfite sequencing (RRBS), the upstream region of the hMSH2 gene was discovered hypermethylated in the platinum-resistant group. The effect of hMSH2 methylation on the cellular response to cisplatin was explored by demethylation and knockdown assays in ovarian cancer cell line A2780. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was employed to examine the methylation levels of hMSH2 upstream region in additional 40 EOC patient samples. RT-qPCR and IHC assay was used to detect the hMSH2 mRNA and protein expression in extended 150 patients. Results RRBS assay discovered an upstream region from − 1193 to − 1125 of hMSH2 was significant hypermethylated in resistant EOC patients (P = 1.06 × 10−14). In vitro analysis demonstrated that global demethylation increased cisplatin sensitivity along with a higher expression of the hMSH2 mRNA and protein. Knockdown hMSH2 reduced the cell sensitivity to cisplatin. MALDI-TOF mass spectrometry assay validated the strong association of hypermethylation of hMSH2 upstream region with platinum resistance. Spearman’s correlation analysis revealed a significantly negative connection between methylation level of hMSH2 upstream region and its expression. The Kaplan-Meier analyses showed the high methylation of hMSH2 promoter region, and its low expressions are associated with worse survival. In multivariable models, hMSH2 low expression was an independent factor predicting poor outcome (P = 0.03, HR = 1.91, 95%CI = 1.85–2.31). Conclusion The hypermethylation of hMSH2 upstream region is associated with platinum resistant in EOC, and low expression of hMSH2 may be an index for the poor prognosis.

scholarly journals Alternative splicing acts as an independent prognosticator in ovarian carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Ouyang ◽  
Kaide Xia ◽  
Xue Yang ◽  
Shichao Zhang ◽  
Li Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Regression Analysis ◽  
Alternative Splicing ◽  
Ovarian Carcinoma ◽  
Cancer Patients ◽  
Cox Regression ◽  
Excision Repair ◽  
Splicing Factors ◽  
Prognostic Signature ◽  
Cox Regression Analysis

AbstractAlternative splicing (AS) events associated with oncogenic processes present anomalous perturbations in many cancers, including ovarian carcinoma. There are no reliable features to predict survival outcomes for ovarian cancer patients. In this study, comprehensive profiling of AS events was conducted by integrating AS data and clinical information of ovarian serous cystadenocarcinoma (OV). Survival-related AS events were identified by Univariate Cox regression analysis. Then, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to construct the prognostic signatures within each AS type. Furthermore, we established a splicing-related network to reveal the potential regulatory mechanisms between splicing factors and candidate AS events. A total of 730 AS events were identified as survival-associated splicing events, and the final prognostic signature based on all seven types of AS events could serve as an independent prognostic indicator and had powerful efficiency in distinguishing patient outcomes. In addition, survival-related AS events might be involved in tumor-related pathways including base excision repair and pyrimidine metabolism pathways, and some splicing factors might be correlated with prognosis-related AS events, including SPEN, SF3B5, RNPC3, LUC7L3, SRSF11 and PRPF38B. Our study constructs an independent prognostic signature for predicting ovarian cancer patients’ survival outcome and contributes to elucidating the underlying mechanism of AS in tumor development.

scholarly journals High expression of fibroblast activation protein (FAP) predicts poor outcome in high-grade serous ovarian cancer

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Min Li ◽  
Xue Cheng ◽  
Rong Rong ◽  
Yan Gao ◽  
Xiuwu Tang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cox Regression ◽  
Paraffin Section ◽  
Progression Free Survival ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Systematic Analysis ◽  
Cox Regression Analysis ◽  
Genes Expression ◽  
High Level

Abstract Background High-grade serous ovarian cancer (HGSOC) is a fatal form of ovarian cancer. Previous studies indicated some potential biomarkers for clinical evaluation of HGSOC prognosis. However, there is a lack of systematic analysis of different expression genes (DEGs) to screen and detect significant biomarkers of HGSOC. Methods TCGA database was conducted to analyze relevant genes expression in HGSOC. Outcomes of candidate genes expression, including overall survival (OS) and progression-free survival (PFS), were calculated by Cox regression analysis for hazard rates (HR). Histopathological investigation of the identified genes was carried out in 151 Chinese HGSOC patients to validate gene expression in different stages of HGSOC. Results Of all 57,331 genes that were analyzed, FAP was identified as the only novel gene that significantly contributed to both OS and PFS of HGSOC. In addition, FAP had a consistent expression profile between carcinoma-paracarcinoma and early-advanced stages of HGSOC. Immunological tests in paraffin section also confirmed that up-regulation of FAP was present in advanced stage HGSOC patients. Prediction of FAP network association suggested that FN1 could be a potential downstream gene which further influenced HGSOC survival. Conclusions High-level expression of FAP was associated with poor prognosis of HGSOC via FN1 pathway.

Identification and Validation of a Seven m6A-related lncRNAs Signature Predicting Prognosis of Ovarian Cancer

2021 ◽  
Author(s):  
Yan Li ◽  
Xiaoying Wang ◽  
Yue Han ◽  
Xun Li
Keyword(s):  
Ovarian Cancer ◽  
Regression Analysis ◽  
Correlation Analysis ◽  
Prognostic Value ◽  
Cox Regression ◽  
Risk Group ◽  
Pearson Correlation ◽  
Regression Analyses ◽  
Cox Regression Analysis ◽  
Pearson Correlation Analysis

Abstract Background: Long non-coding RNAs (lncRNAs) play an important role in angiogenesis, immune response, inflammatory response and tumor development and metastasis. m6 A (N6 - methyladenosine) is one of the most common RNA modifications in eukaryotes. The aim of our research was to investigate the potential prognostic value of m6A-related lncRNAs in ovarian cancer (OC).Methods: The data we need for our research was downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Pearson correlation analysis between 21 m6A regulators and lncRNAs was performed to identify m6A-related lncRNAs. Univariate Cox regression analysis was implemented to screen for lncRNAs with prognostic value. A least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analyses was used to further reduct the lncRNAs with prognostic value and construct a m6A-related lncRNAs signature for predicting the prognosis of OC patients. Results: 275 m6A-related lncRNAs were obtained using pearson correlation analysis. 29 m6A-related lncRNAs with prognostic value was selected through univariate Cox regression analysis. Then, a seven m6A-related lncRNAs signature was identified by LASSO Cox regression. Each patient obtained a riskscore through multivariate Cox regression analyses and the patients were classified into high-and low-risk group using the median riskscore as a cutoff. Kaplan-Meier curve revealed that the patients in high-risk group have poor outcome. The receiver operating characteristic curve revealed that the predictive potential of the m6A-related lncRNAs signature for OC was powerful. The predictive potential of the m6A-related lncRNAs signature was successfully validated in the GSE9891, GSE26193 datasets and our clinical specimens. Multivariate analyses suggested that the m6A-related lncRNAs signature was an independent prognostic factor for OC patients. Moreover, a nomogram based on the expression level of the seven m6A-related lncRNAs was established to predict survival rate of patients with OC. Finally, a competing endogenous RNA (ceRNA) network associated with the seven m6A-related lncRNAs was constructed to understand the possible mechanisms of the m6A-related lncRNAs involed in the progression of OC.Conclusions: In conclusion, our research revealed that the m6A-related lncRNAs may affect the prognosis of OC patients and identified a seven m6A-related lncRNAs signature to predict the prognosis of OC patients.

scholarly journals Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5824-5831 ◽  
Author(s):  
Ana Flávia Tibúrcio Ribeiro ◽  
Marta Pratcorona ◽  
Claudia Erpelinck-Verschueren ◽  
Veronika Rockova ◽  
Mathijs Sanders ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Gene Expression Signature ◽  
Mutation Status ◽  
Cox Regression Analysis ◽  
Prognostic Effect ◽  
Or Gene ◽  
Acute Myeloid

Abstract The prevalence, the prognostic effect, and interaction with other molecular markers of DNMT3A mutations was studied in 415 patients with acute myeloid leukemia (AML) younger than 60 years. We show mutations in DNMT3A in 96 of 415 patients with newly diagnosed AML (23.1%). Univariate Cox regression analysis showed that patients with DNMT3Amutant AML show significantly worse overall survival (OS; P = .022; hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.04-1.81), and relapse-free survival (RFS; P = .005; HR, 1.52; 95% CI, 1.13-2.05) than DNMT3Awild-type AMLs. In a multivariable analysis, DNMT3A mutations express independent unfavorable prognostic value for OS (P = .003; HR, 1.82; 95% CI, 1.2-2.7) and RFS (P < .001; HR, 2.2; 95% CI, 1.4-3.3). In a composite genotypic subset of cytogenetic intermediate-risk AML without FLT3-ITD and NPM1 mutations, this association is particularly evident (OS: P = .013; HR, 2.09; 95% CI, 1.16-3.77; RFS: P = .001; HR, 2.65; 95% CI, 1.48-4.89). The effect of DNMT3A mutations in human AML remains elusive, because DNMT3Amutant AMLs did not express a methylation or gene expression signature that discriminates them from patients with DNMT3Awild-type AML. We conclude that DNMT3A mutation status is an important factor to consider for risk stratification of patients with AML.

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