scholarly journals Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification

2022 ◽  
Author(s):  
Robert L Hollis ◽  
Alison M Meynert ◽  
Caroline O Michie ◽  
Tzyvia Rye ◽  
Michael Churchman ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Ovarian Carcinoma ◽  
Copy Number ◽  
Immune Cell ◽  
Hazard Ratio ◽  
High Grade ◽  
Serous Ovarian Carcinoma ◽  
Molecular Landscape ◽  
The Relationship

Background: High grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer; most patients experience disease recurrence which accumulates chemoresistance, leading to treatment failure. Previous investigations have characterised HGSOC at the genomic and transcriptomic level, identifying subtypes of patients with differential outcome and treatment response. However, the relationship between molecular events identified at the gene sequence, gene copy number and gene expression levels remains poorly defined. Methods: We perform multi-layer molecular characterisation of a large retrospective HGSOC cohort (n=362) with detailed clinical annotation to interrogate the relationship between patient groups defined by gene mutation, copy number events, gene expression patterns and infiltrating immune cell burden. We construct a high resolution picture of the molecular landscape in HGSOC and identify features of tumours associated with distinct clinical behaviour in patients. Results: BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival (multivariable hazard ratio 0.40 and 0.53) and higher chemotherapy response rates at first- and second-line treatment. CCNE1-gained (CCNE1g) cases demonstrated shorter survival (multivariable hazard ratio 1.52, 95% CI 1.10-2.10), under-representation of FIGO stage IV cases (P=0.017) and no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and derived subtypes: the TCGA DIF, IMR, PRO and MES subtypes correlated with the Tothill C4, C2, C5 and C1 subtypes (P<0.001). IMR/C2 cases displayed higher BRCA1/2m frequency (25.5% and 32.5%) and significantly greater infiltration of immune cells (P<0.001), while PRO/C5 cases had the highest CCNE1g rate (23.9% and 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (hazard ratio range 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations (P=0.005); RB loss was further associated with favourable survival within cases harbouring HRR aberrations (multivariable hazard ratio 0.50, 95% CI 0.30-0.84). Conclusions: These data paint a high resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.

scholarly journals Digital Immune-Related Gene Expression Signatures In High-Grade Serous Ovarian Carcinoma: Developing Prediction Models For Platinum Response

2019 ◽  
Vol Volume 11 ◽  
pp. 9571-9583
Author(s):  
Fabian Mairinger ◽  
Agnes Bankfalvi ◽  
Kurt Werner Schmid ◽  
Elena Mairinger ◽  
Pawel Mach ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Carcinoma ◽  
Prediction Models ◽  
High Grade ◽  
Related Gene ◽  
Serous Ovarian Carcinoma ◽  
Immune Related Gene ◽  
Gene Expression Signatures

scholarly journals Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

PLoS ONE ◽  
2012 ◽  
Vol 7 (3) ◽  
pp. e34546 ◽  
Author(s):  
Chad J. Creighton ◽  
Anadulce Hernandez-Herrera ◽  
Anders Jacobsen ◽  
Douglas A. Levine ◽  
Parminder Mankoo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Carcinoma ◽  
High Grade ◽  
Serous Ovarian Carcinoma

scholarly journals Histone methyltransferases EHMT1 and EHMT2 (GLP/G9A) maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Zachary L. Watson ◽  
Tomomi M. Yamamoto ◽  
Alexandra McMellen ◽  
Hyunmin Kim ◽  
Connor J. Hughes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Ovarian Carcinoma ◽  
Immunofluorescent Staining ◽  
High Grade ◽  
Rna Seq ◽  
Serous Ovarian Carcinoma ◽  
Resistant Cells

Abstract Background Euchromatic histone-lysine-N-methyltransferases 1 and 2 (EHMT1/2, aka GLP/G9A) catalyze dimethylation of histone H3 lysine 9 (H3K9me2) and have roles in epigenetic silencing of gene expression. EHMT1/2 also have direct roles in DNA repair and are implicated in chemoresistance in several cancers. Resistance to chemotherapy and PARP inhibitors (PARPi) is a major cause of mortality in high-grade serous ovarian carcinoma (HGSOC), but the contribution of the epigenetic landscape is unknown. Results To identify epigenetic mechanisms of PARPi resistance in HGSOC, we utilized unbiased exploratory techniques, including RNA-Seq and mass spectrometry profiling of histone modifications. Compared to sensitive cells, PARPi-resistant HGSOC cells display a global increase of H3K9me2 accompanied by overexpression of EHMT1/2. EHMT1/2 overexpression was also observed in a PARPi-resistant in vivo patient-derived xenograft (PDX) model. Genetic or pharmacologic disruption of EHMT1/2 sensitizes HGSOC cells to PARPi. Cell death assays demonstrate that EHMT1/2 disruption does not increase PARPi-induced apoptosis. Functional DNA repair assays show that disruption of EHMT1/2 ablates homologous recombination (HR) and non-homologous end joining (NHEJ), while immunofluorescent staining of phosphorylated histone H2AX shows large increases in DNA damage. Propidium iodide staining and flow cytometry analysis of cell cycle show that PARPi treatment increases the proportion of PARPi-resistant cells in S and G2 phases, while cells treated with an EHMT1/2 inhibitor remain in G1. Co-treatment with PARPi and EHMT1/2 inhibitor produces an intermediate phenotype. Immunoblot of cell cycle regulators shows that combined EHMT1/2 and PARP inhibition reduces expression of specific cyclins and phosphorylation of mitotic markers. These data suggest DNA damage and altered cell cycle regulation as mechanisms of sensitization. RNA-Seq of PARPi-resistant cells treated with EHMT1/2 inhibitor showed significant gene expression changes enriched in pro-survival pathways that remain unexplored in the context of PARPi resistance, including PI3K, AKT, and mTOR. Conclusions This study demonstrates that disrupting EHMT1/2 sensitizes HGSOC cells to PARPi, and suggests a potential mechanism through DNA damage and cell cycle dysregulation. RNA-Seq identifies several unexplored pathways that may alter PARPi resistance. Further study of EHMT1/2 and regulated genes will facilitate development of novel therapeutic strategies to successfully treat HGSOC.

scholarly journals Oncogenic B-Myb Is Associated With Deregulation of the DREAM-Mediated Cell Cycle Gene Expression Program in High Grade Serous Ovarian Carcinoma Clinical Tumor Samples

2021 ◽  
Vol 11 ◽  
Author(s):  
Audra N. Iness ◽  
Lisa Rubinsak ◽  
Steven J. Meas ◽  
Jessica Chaoul ◽  
Sadia Sayeed ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Ovarian Carcinoma ◽  
Treatment Response ◽  
Target Genes ◽  
Gene Expression Signature ◽  
Cell Cycle Gene ◽  
High Grade ◽  
Serous Ovarian Carcinoma ◽  
Cell Cycle Gene Expression

Cell cycle control drives cancer progression and treatment response in high grade serous ovarian carcinoma (HGSOC). MYBL2 (encoding B-Myb), an oncogene with prognostic significance in several cancers, is highly expressed in most HGSOC cases; however, the clinical significance of B-Myb in this disease has not been well-characterized. B-Myb is associated with cell proliferation through formation of the MMB (Myb and MuvB core) protein complex required for transcription of mitotic genes. High B-Myb expression disrupts the formation of another transcriptional cell cycle regulatory complex involving the MuvB core, DREAM (DP, RB-like, E2F, and MuvB), in human cell lines. DREAM coordinates cell cycle dependent gene expression by repressing over 800 cell cycle genes in G0/G1. Here, we take a bioinformatics approach to further evaluate the effect of B-Myb expression on DREAM target genes in HGSOC and validate our cellular model with clinical specimens. We show that MYBL2 is highly expressed in HGSOC and correlates with expression of DREAM and MMB target genes in both The Cancer Genome Atlas (TCGA) as well as independent analyses of HGSOC primary tumors (N = 52). High B-Myb expression was also associated with poor overall survival in the TCGA cohort and analysis by a DREAM target gene expression signature yielded a negative impact on survival. Together, our data support the conclusion that high expression of MYBL2 is associated with deregulation of DREAM/MMB-mediated cell cycle gene expression programs in HGSOC and may serve as a prognostic factor independent of its cell cycle role. This provides rationale for further, larger scale studies aimed to determine the clinical predictive value of the B-Myb gene expression signature for treatment response as well as patient outcomes.

scholarly journals Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

2020 ◽  
Vol 26 (20) ◽  
pp. 5411-5423 ◽  
Author(s):  
Aline Talhouk ◽  
Joshy George ◽  
Chen Wang ◽  
Timothy Budden ◽  
Tuan Zea Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Carcinoma ◽  
Molecular Subtype ◽  
High Grade ◽  
Serous Ovarian Carcinoma ◽  
Development And Validation

scholarly journals Combined PD-1/PD-L1 and tumor-infiltrating immune cells redefined a unique molecular subtype of high-grade serous ovarian carcinoma

BMC Genomics ◽  
2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Ping Liu ◽  
Ruoxu Chen ◽  
Xudong Zhang ◽  
Ruiting Fu ◽  
Lin Tao ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Immune Cell ◽  
Molecular Subtype ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
High Grade ◽  
Serous Ovarian Carcinoma ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Antigen Presenting

Abstract Background High-grade serous ovarian carcinoma is highly heterogeneous, and although many studies have been conducted to identify high-grade serous ovarian carcinoma molecular subtypes that are sensitive to immunotherapy, no precise molecular subtype has been proposed to date. Immune cell infiltration and immune checkpoints are highly correlated with immunotherapy. Here, we investigated immune cell infiltration and immune checkpoint values for prognosis and precise immunotherapy for high-grade serous ovarian carcinoma based on molecular subtype classification. Results “High antigen-presenting cells infiltration molecular subtype of high-grade serous ovarian carcinoma” was identified in immune cell infiltration profiles. Each of the three immune cell infiltration clusters (A, B, and C) demonstrated distinct immune cell characterization, with immune cell infiltration cluster C exhibiting high antigen-presenting cell infiltration, improved prognosis, and higher sensitivity to immunotherapy. Programmed death-1/programmed death ligand 1 has a prognostic and predictive role that can help classify molecular subtypes. Conclusions Our findings redefined a unique molecular subtype of high-grade serous ovarian carcinoma, suggesting that high-grade serous ovarian carcinoma patients with higher antigen-presenting cell infiltration and programmed death-1/programmed death ligand 1 expression can benefit from precise immunotherapy.

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