Differentially expressed genes in platinum-resistant high-grade serous ovarian cancer

This study aims to identify differentially expressed proteins related with platinum sensitivity and to find biomarkers for predicting platinum response and survival outcomes in patients with high-grade serous ovarian cancer (HGSOC). Eligible HGSOC patients were divided into platinum-sensitive and platinum-resistant groups according to platinum-free interval (PFI). Tissue protein lysates from tumor tissues were subjected to an in-solution tryptic digest followed by tandem mass tag (TMT) labeling of the resulting peptides and mass spectrometric analysis. Candidate proteins were identified using differentially expressed protein and gene set enrichment analysis (GSEA) and confirmed by immunohistochemistry (IHC), and their survival relevance was evaluated in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. The results showed that there was a significant difference in the protein expression profiling between the two patient groups. In the GSEA model, a gene set of 239 extracellular matrix (ECM)-related proteins was significantly enriched in the platinum-sensitive group [normalized enrichment score (NES) = 3.82, q < 10−5], and this finding was confirmed in TCGA ovarian cancer cohort. Interestingly, an ECM-related gene expression, serpin family A member 10 (SERPINA10), was identified to be significantly positively correlated with overall survival (OS) and progression-free survival (PFS) in TCGA ovarian cancer cohort (all p < 0.05). IHC results demonstrated that HGSOC patients with high SERPINA10 expression had longer PFI than the patients with low SERPINA10 expression (9 vs. 5 months, p = 0.038), and the SERPINA10 expression had an area under the receiver operating characteristic curve (AUC) value of 0.758 (95% CI = 0.612–0.905; p = 0.005) to discriminate the platinum-sensitive group from the platinum-resistant group. In conclusion, the results suggested that SERPINA10 could be a promising biomarker for predicting the response and survival in platinum-based chemotherapy of HGSOC.

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

Genome Medicine ◽

10.1186/s13073-020-00786-7 ◽

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.

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

10.31219/osf.io/uwjt4 ◽

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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Frizzled class 7 receptor is differentially expressed in high-grade serous ovarian cancer and based on patient survival.

10.31219/osf.io/aqzj9 ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Progression Free Survival ◽

Global Gene Expression ◽

Differentially Expressed ◽

Published Data ◽

High Grade ◽

Serous Ovarian Cancer ◽

Free Survival

High-grade serous ovarian cancer (HGSC) is the most common type of the most lethal gynecologic malignancy (1). To identify genes whose expression was associated with survival outcomes in HGSC, we used published data from patients enrolled in the ICON7 trial to compare the global gene expression profiles of primary HGSC tumors from women with the best and worst progression-free survival (PFS) (2). We found that the Frizzled class 7 (Fzd7) receptor was among the genes most differentially expressed in HGSC tumors when comparing tumor transcriptomes based on superior or inferior PFS. In two independent datasets, Fzd7 was among the genes most differentially expressed in HGSC tumors when comparing primary tumor to the normal ovary (3, 4). Wnt pathway signaling through Fzd7 may be relevant to the biology of high-grade serous ovarian cancers.

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Abstract NT-106: PIN1: A PROMISING TARGET FOR PLATINUM-RESISTANT HIGH GRADE SEROUS OVARIAN CANCER

10.1158/1557-3265.ovcasymp18-nt-106 ◽

2019 ◽

Author(s):

Concetta Russo Spena ◽

Lucia De Stefano ◽

Barbara Salis ◽

Carlotta Granchi ◽

Maguie El Boustani ◽

...

Keyword(s):

Ovarian Cancer ◽

High Grade ◽

Serous Ovarian Cancer ◽

Platinum Resistant ◽

Promising Target

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Abstract AP23: A PLATINUM–RESISTANT SUBTYPE OF HIGH–GRADE SEROUS OVARIAN CANCER IDENTIFIED BY A NETWORK OF SOMATIC MUTATIONS

10.1158/1557-3265.ovcasymp16-ap23 ◽

2017 ◽

Author(s):

John Paul Shen ◽

Ana Bojorquez-Gomez ◽

Justin Huang ◽

Matan Hofree ◽

Kristin Klepper ◽

...

Keyword(s):

Ovarian Cancer ◽

Somatic Mutations ◽

High Grade ◽

Serous Ovarian Cancer ◽

Platinum Resistant

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Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study

Biomedicines ◽

10.3390/biomedicines9010055 ◽

2021 ◽

Vol 9 (1) ◽

pp. 55

Author(s):

Francesco Plotti ◽

Corrado Terranova ◽

Federica Guzzo ◽

Carlo De Cicco Nardone ◽

Daniela Luvero ◽

...

Keyword(s):

Ovarian Cancer ◽

Brca Mutation ◽

Predictive Marker ◽

Chemotherapy Response ◽

High Grade ◽

Serous Ovarian Cancer ◽

Wild Type ◽

Platinum Sensitive ◽

Platinum Resistant

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.

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An integrated approach for identifying genes associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer

Advances in Modern Oncology Research ◽

10.18282/amor.v3.i1.173 ◽

2017 ◽

Vol 3 (1) ◽

pp. 31

Author(s):

Ahmed Hossain ◽

Gias Uddin Ahsan ◽

Hayatun Nabi

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Statistical Methods ◽

Differentially Expressed Genes ◽

Differentially Expressed ◽

Sparse Pca ◽

Platinum Sensitive ◽

New Genes ◽

Platinum Resistant ◽

Serous Epithelial Ovarian Cancer

Treatment with chemotherapy is important in limiting the intensity of serous epithelial ovarian cancer. However, not all patients are sensitive to platinum chemotherapy corresponding to longer progression-free survival (PFS >8 months). Koti et al.[1] revealed a set of 204 discriminating genes possessing expression levels, which could influence differential chemotherapy response between the platinum-resistant and platinum-sensitive group of patients. They considered Welch two-sample t-test and non-parametric Mann-Whitney U test to identify the differentially expressed genes. However, both the statistical methods turned out to be unsuitable for microarray data. In this paper, we used three alternative statistical methods to select a combined list of genes and compared the genes that were proposed by Koti et al.[1]. Subsequently, we recommended using sparse principal component analysis (sparse PCA) to identify a final list of genes. Sparse PCA incorporates correlation into account among the genes and helps to draw a biologically important gene discovery. We identified 77 differentially expressed genes, which include 11 new genes that can separate the groups of patients who are platinum-resistant and platinum-sensitive to the chemotherapy. The integrative approach can also be effective in another high dimensional dataset to compare between two groups.

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