scholarly journals Integrated bioinformatic analysis identifies UBE2Q1 as a potential prognostic marker for high grade serous ovarian cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rachel Topno ◽  
Ibha Singh ◽  
Manoj Kumar ◽  
Pallavi Agarwal
Keyword(s):  
Ovarian Cancer ◽  
Prognostic Marker ◽  
Expression Analysis ◽  
Expression Patterns ◽  
Prognostic Impact ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Potential Biomarker

Abstract Background High grade serous ovarian cancer (HGSOC) accounts for nearly 60% of total cases of epithelial ovarian cancer. It is the most aggressive subtype, which shows poor prognosis and low patient survival. For better management of HGSOC patients, new prognostic biomarkers are required to facilitate improved treatment strategies and ensure suitable healthcare decisions. Methods We performed genome wide expression analysis of HGSOC patient samples to identify differentially expressed genes (DEGs) using R based Limma package, Clust and other statistical tools. The identified DEGs were subjected to weighted gene co-expression network analysis (WGCNA) to identify co-expression patterns of relevant genes. Module trait and gene ontology analyses were performed to establish important gene co-expression networks and their biological functions. Overlapping the most relevant DEG cluster 4 with prominent WGCNA cyan module identified strongest correlation of UBE2Q1 with ovarian cancer and its prognostic significance on survival probability of ovarian cancer patients was investigated. The predictive value of UBE2Q1 as a potential biomarker was analysed by correlating its expression with 12-months relapse free survival of patients in response to platin/taxane, the standard first-line chemotherapy for ovarian cancer, and analysing area under the ROC curve. Results An integrated gene expression analysis and WGCNA, identified UBE2Q1 as a potential prognostic marker associated with poor relapse-free survival and response outcome to platin/taxane treatment of patients with high grade serous ovarian cancer. Conclusions Our study identifies a potential UBE2Q1 – B4GALT3 functional axis in ovarian cancer, where only the E2 conjugating enzyme showed a poor prognostic impact on the disease.

scholarly journals KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Marta De Donato ◽  
Gabriele Babini ◽  
Simona Mozzetti ◽  
Marianna Buttarelli ◽  
Alessandra Ciucci ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Prognostic Marker ◽  
Late Stage ◽  
Therapeutic Target ◽  
Family Members ◽  
High Grade ◽  
Serous Ovarian Cancer

Abstract Background In spite of great progress in the surgical and clinical management, until now no significant improvement in overall survival of High-Grade Serous Ovarian Cancer (HGSOC) patients has been achieved. Important aspects for disease control remain unresolved, including unclear pathogenesis, high heterogeneity and relapse resistance after chemotherapy. Therefore, further research on molecular mechanisms involved in cancer progression are needed to find new targets for disease management. The Krüppel-like factors (KLFs) are a family of transcriptional regulators controlling several basic cellular processes, including proliferation, differentiation and migration. They have been shown to play a role in various cancer-relevant processes, in a context-dependent way. Methods To investigate a possible role of KLF family members as prognostic biomarkers, we carried out a bioinformatic meta-analysis of ovarian transcriptome datasets in different cohorts of late-stage HGSOC patients. In vitro cellular models of HGSOC were used for functional studies exploring the role of KLF7 in disease development and progression. Finally, molecular modelling and virtual screening were performed to identify putative KLF7 inhibitors. Results Bioinformatic analysis highlighted KLF7 as the most significant prognostic gene, among the 17 family members. Univariate and multivariate analyses identified KLF7 as an unfavourable prognostic marker for overall survival in late-stage TCGA-OV and GSE26712 HGSOC cohorts. Functional in vitro studies demonstrated that KLF7 can play a role as oncogene, driving tumour growth and dissemination. Mechanistic targets of KLF7 included genes involved in epithelial to mesenchymal transition, and in maintaining pluripotency and self-renewal characteristics of cancer stem cells. Finally, in silico analysis provided reliable information for drug-target interaction prediction. Conclusions Results from the present study provide the first evidence for an oncogenic role of KLF7 in HGSOC, suggesting it as a promising prognostic marker and therapeutic target.

scholarly journals A cell-of-origin epigenetic tracer reveals clinically distinct subtypes of high-grade serous ovarian cancer

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Pietro Lo Riso ◽  
Carlo Emanuele Villa ◽  
Gilles Gasparoni ◽  
Andrea Vingiani ◽  
Raffaele Luongo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Methylation ◽  
Differentially Expressed ◽  
Prognostic Impact ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Tumor Subtypes ◽  
Transcriptional Alterations ◽  
Bona Fide ◽  
Tissue Of Origin

Abstract Background High-grade serous ovarian cancer (HGSOC) is a major unmet need in oncology. The remaining uncertainty on its originating tissue has hampered the discovery of molecular oncogenic pathways and the development of effective therapies. Methods We used an approach based on the retention in tumors of a DNA methylation trace (OriPrint) that distinguishes the two putative tissues of origin of HGSOC, the fimbrial (FI) and ovarian surface epithelia (OSE), to stratify HGSOC by several clustering methods, both linear and non-linear. The identified tumor subtypes (FI-like and OSE-like HGSOC) were investigated at the RNAseq level to stratify an in-house cohort of macrodissected HGSOC FFPE samples to derive overall and disease-free survival and identify specific transcriptional alterations of the two tumor subtypes, both by classical differential expression and weighted correlation network analysis. We translated our strategy to published datasets and verified the co-occurrence of previously described molecular classification of HGSOC. We performed cytokine analysis coupled to immune phenotyping to verify alterations in the immune compartment associated with HGSOC. We identified genes that are both differentially expressed and methylated in the two tumor subtypes, concentrating on PAX8 as a bona fide marker of FI-like HGSOC. Results We show that: - OriPrint is a robust DNA methylation tracer that exposes the tissue of origin of HGSOC. - The tissue of origin of HGSOC is the main determinant of DNA methylation variance in HGSOC. - The tissue of origin is a prognostic factor for HGSOC patients. - FI-like and OSE-like HGSOC are endowed with specific transcriptional alterations that impact patients’ prognosis. - OSE-like tumors present a more invasive and immunomodulatory phenotype, compatible with its worse prognostic impact. - Among genes that are differentially expressed and regulated in FI-like and OSE-like HGSOC, PAX8 is a bona fide marker of FI-like tumors. Conclusions Through an integrated approach, our work demonstrates that both FI and OSE are possible origins for human HGSOC, whose derived subtypes are both molecularly and clinically distinct. These results will help define a new roadmap towards rational, subtype-specific therapeutic inroads and improved patients’ care.

scholarly journals Prognostic value of kallikrein-related peptidase 7 (KLK7) mRNA expression in advanced high-grade serous ovarian cancer

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Weiwei Gong ◽  
Yueyang Liu ◽  
Eleftherios P. Diamandis ◽  
Marion Kiechle ◽  
Holger Bronger ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Protein Level ◽  
Multivariate Analyses ◽  
Expression Patterns ◽  
Mrna Levels ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Expression Levels ◽  
Mrna Expression Levels

Abstract Background High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer. A growing body of evidence suggests tumor-supporting roles of several members of the kallikrein-related peptidase (KLK) family, including KLK5 and KLK7, in this cancer subtype. In normal physiology, KLK5 and KLK7 are the major proteases involved in skin desquamation. Moreover, in several cancer types KLK5 and KLK7 co-expression has been observed. Recently, we have shown that elevated KLK5 mRNA levels are associated with an unfavorable prognosis in HGSOC. Therefore, the aim of this study was to investigate the clinical significance of KLK7 mRNA expression and to explore its relation to KLK5 levels in HGSOC. Methods mRNA expression levels of KLK7 were quantified by qPCR in a well-characterized patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO III/IV, n = 139). Previously determined KLK5 mRNA as well as KLK5 and KLK7 antigen concentrations were used to evaluate the relationship between the expression patterns of both factors on the mRNA as well as protein level in tumor tissue of HGSOC patients. Results There were strong, significant positive correlations between KLK5 and KLK7 both at the mRNA and the protein level, suggesting coordinate expression of these proteases in HGSOC. In univariate analyses, elevated KLK7 levels as well as the combination of KLK5 + KLK7 (high and/or high versus low/low) were significantly associated with worse progression-free survival (PFS). High mRNA expression levels of KLK7 and the combination of KLK5 and KLK7 showed a trend towards significance for overall survival (OS). In multivariate analyses, KLK7 mRNA expression represented an unfavorable, statistically significant independent predictor for PFS and OS. Conclusions The findings imply that both increased KLK5 and KLK7 mRNA expression levels represent unfavorable prognostic biomarkers in advanced high-grade serous ovarian cancer, whereby multivariate analyses indicate that KLK7 mRNA exhibits a stronger predictive value as compared to KLK5 mRNA and the combination of KLK5 and KLK7.

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 A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Panagiotis A. Konstantinopoulos ◽  
Alexandre André B. A. da Costa ◽  
Doga Gulhan ◽  
Elizabeth K. Lee ◽  
Su-Chun Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Progression Free Survival ◽  
Replication Stress ◽  
Inhibitor Therapy ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Free Survival ◽  
Rb Pathway ◽  
Pathway Regulation ◽  
Stress Biomarker

AbstractIn a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17–0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13–0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47–2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.

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