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

2018 ◽  
Author(s):  
Pietro Lo Riso ◽  
Carlo Emanuele Villa ◽  
Gilles Gasparoni ◽  
Raffaele Luongo ◽  
Anna Manfredi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unmet Need ◽  
Prognostic Impact ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cell Of Origin ◽  
Oncogenic Pathways ◽  
Transcriptomic Signature ◽  
A Cell ◽  
Disease Subtypes

AbstractHigh grade serous ovarian cancer (HGSOC) is a major unmet need in oncology. The persistent uncertainty on its originating tissue has contributed to hamper the discovery of oncogenic pathways and effective therapies. Here we define the DNA methylation print that distinguishes the human fimbrial (FI) and ovarian surface epithelia (OSE) and develop a robust epigenetic cell-of-origin tracer that stratifies HGSOC in FI-and OSE-originated tumors across all available cohorts. We translate this origin-based stratification into a clinically actionable transcriptomic signature, demonstrating its prognostic impact on patients’ survival and identifying novel network level dysregulations specific for the two disease subtypes.

The developmental origins of high grade serous ovarian cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17063-e17063
Author(s):  
Pietro Lo Riso ◽  
Carlo Emanuele Villa ◽  
Gilles Gasparoni ◽  
Raffaele Luongo ◽  
Anna Manfredi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Surface Epithelium ◽  
Transcriptional Networks ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cell Of Origin ◽  
Clustering Methods ◽  
Alternative Clustering ◽  
Molecular Features ◽  
A Cell

e17063 Background: The still persistent uncertainty in the identification of the cell of origin of high grade serous ovarian cancer (HGSOC), with two candidate originating tissues identified in the distal tract of the fallopian tube (FI) and the surface epithelium of the ovary (OSE), has hampered the identification of clinically relevant molecular features for this disease to be targeted for therapy. This resulted in only a negligible improvement in patient’s care since the introduction of carboplatin-based treatments. Methods: To solve this issue, here we show an innovative method based on the identification of a cell of origin-specific DNA methylation print (OriPrint) that allows the reliable stratification of human primary HGSOC in FI and OSE-originated tumors. Results: We show that this approach is robust to alternative clustering methods and can discriminate tumors derived from each of the two origins across different datasets. Also, we translated these findings on a well-characterized retrospective cohort, showing that the cell of origin significantly impacts patient’s prognosis. Finally, through RNAseq, we unveil origin-specific transcriptional networks compatible with the differential impact on patient’s survival, mainly involved in inflammatory response and cell survival, movement and signaling. Conclusions: Our approach proves for the first time in human primary samples that both origins can give rise to HGSOC, paving the way to a finer molecular characterization of this disease and to the development of more effective therapeutic regimens for improved care for patients.

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 Integrated Molecular Profiling Studies to Characterize the Cellular Origins of High-Grade Serous Ovarian Cancer

2018 ◽  
Author(s):  
Kate Lawrenson ◽  
Marcos A.S. Fonseca ◽  
Felipe Segato ◽  
Janet M. Lee ◽  
Rosario I. Corona ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Cells ◽  
Tumor Development ◽  
Molecular Profiling ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cell Of Origin ◽  
Ovarian Cancers ◽  
Integrative Analyses ◽  
Ovarian Surface Epithelial

AbstractHistorically, high-grade serous ovarian cancers (HGSOCs) were thought to arise from ovarian surface epithelial cells (OSECs) but recent data implicate fallopian tube secretory epithelial cells (FTSECs) as the major precursor. We performed transcriptomic and epigenomic profiling to characterize molecular similarities between OSECs, FTSECs and HGSOCs. Transcriptomic signatures of FTSECs were preserved in most HGSOCs reinforcing FTSECs as the predominant cell-of-origin; though an OSEC-like signature was associated with increased chemosensitivity (Padj= 0.03) and was enriched in proliferative-type tumors, suggesting a dualistic model for HGSOC origins. More super-enhancers (SEs) were shared between FTSECs and HGSOCs than between OSECS and HGSOCs (P< 2.2 × 10−16). SOX18, ELF3 and EHF transcription factors (TFs) coincided with HGSOC SEs and represent putative novel drivers of tumor development. Our integrative analyses support a predominantly fallopian origin for HGSOCs and indicate tumorigenesis may be driven by different TFs according to cell-of-origin.

scholarly journals UnPAXing the Divergent Roles of PAX2 and PAX8 in High-Grade Serous Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 262 ◽  
Author(s):  
Laura Hardy ◽  
Amrita Salvi ◽  
Joanna Burdette
Keyword(s):  
Ovarian Cancer ◽  
Fallopian Tube ◽  
Cancer Progression ◽  
Drug Targets ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cell Of Origin ◽  
Pax8 Expression

High-grade serous ovarian cancer is a deadly disease that can originate from the fallopian tube or the ovarian surface epithelium. The PAX (paired box) genes PAX2 and PAX8 are lineage-specific transcription factors required during development of the fallopian tube but not in the development of the ovary. PAX2 expression is lost early in serous cancer progression, while PAX8 is expressed ubiquitously. These proteins are implicated in migration, invasion, proliferation, cell survival, stem cell maintenance, and tumor growth. Hence, targeting PAX2 and PAX8 represents a promising drug strategy that could inhibit these pro-tumorigenic effects. In this review, we examine the implications of PAX2 and PAX8 expression in the cell of origin of serous cancer and their potential efficacy as drug targets by summarizing their role in the molecular pathogenesis of ovarian cancer.

scholarly journals Prognostic impact of tumor-infiltrating lymphocytes in high grade serous ovarian cancer: a systematic review and meta-analysis

2020 ◽  
Vol 12 ◽  
pp. 175883592096724
Author(s):  
Jiatao Hao ◽  
Hui Yu ◽  
Taohong Zhang ◽  
Ruifang An ◽  
Yan Xue
Keyword(s):  
Systematic Review ◽  
Ovarian Cancer ◽  
Multivariate Analysis ◽  
Meta Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Extensive Literature ◽  
Prognostic Impact ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Infiltrating Lymphocytes

Background: Tumor-infiltrating lymphocytes (TILs) are involved in the antitumor immune response. The association between prognosis in patients with TILs and high-grade serous ovarian cancer (HGSOC) remains obscure, with some studies reporting conflicting results. Methods: We conducted an extensive literature search of electronic databases and retrieved prognostic data of each selected subtype of TILs, including CD3+, CD4+, CD8+, CD103+, and PD-1+ TILs. The fixed-effects model was applied to derive the pooled hazard ratio (HR) and 95% confidence interval (CI) of these markers. Results: The systematic review process yielded 19 eligible studies comprising 6004 patients with HGSOC. We compared TIL-positive and TIL-negative patients, and the pooled HRs from the multivariate analysis revealed that intraepithelial CD8+ TILs were positively correlated with progression-free survival (PFS, HR 0.46, 95% CI 0.25–0.67) and overall survival (OS, HR 0.90, 95% CI 0.86–0.9); stromal CD8+ TILs were positively correlated with OS (HR 0.61, 95% CI 0.36–0.87). Furthermore, the pooled HRs from univariate analysis demonstrated that intraepithelial CD3+, CD4+, CD8+, and CD103+ TILs were positively associated with OS (HR 0.58, 95% CI 0.44–0.72; HR 0.37, 95% CI 0.16–0.59; HR 0.51, 95% CI 0.42–0.60, and HR 0.59, 95% CI 0.44–0.74, respectively); stromal CD4+ and CD8+ TILs were significantly associated with OS (HR 0.63, 95% CI 0.32–0.94 and HR 0.78, 95% CI 0.58–0.97, respectively). However, the pooled HR from the multivariate analysis revealed that PD-1+ TILs were not associated with the OS of patients with HGSOC (HR 0.97, 95% CI 0.90–1.04). Conclusion: This meta-analysis provided evidence of the association of CD3+, CD4+, CD8+, and CD103+ TILs with the survival benefits (OS and PFS) of patients with HGSOC.

Abstract 2068: Cyclooxygenase-1 gene expression contributes to multiple oncogenic pathways in high grade serous ovarian cancer

2015 ◽  
Author(s):  
Andrew J. Wilson ◽  
Brian D. Lehmann ◽  
Jeanette Saskowski ◽  
MD Jashim Uddin ◽  
Cristina Daniel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cyclooxygenase 1 ◽  
Oncogenic Pathways

scholarly journals Platinum resistance induces diverse evolutionary trajectories in high grade serous ovarian cancer

2020 ◽  
Author(s):  
J.I. Hoare ◽  
H. Hockings ◽  
J. Saxena ◽  
V.L. Silva ◽  
E. Maniati ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Dna Recombination ◽  
Unmet Need ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Platinum Resistant ◽  
Recombination Pathway

AbstractResistance to therapy is an enduring challenge in cancer care. Here we interrogate this critical unmet need using high grade serous ovarian cancer (HGSC) as a disease model. We have generated a unique panel of platinum-resistant HGSC models and shown that they share multiple transcriptomic features with relapsed human HGSC. Moreover, they evolve diverse in vivo phenotypes reflecting the human disease. We previously characterised copy number signatures in HGSC that correlate with patient survival and now provide the first evidence that these signatures undergo recurrent alterations during platinum therapy. Furthermore, specific, resistance-associated signature change is associated with functionally relevant gene expression differences. For example, reduced signature 3 (BRCA1/2-related homologous recombination deficiency) is associated with increased expression of homologous recombination repair genes (Rad51C, Rad51D, BRCA1) and DNA recombination pathway enrichment. Our mechanistic examination therefore provides new and clinically relevant insights into the genomic evolution of platinum-resistant cancers.

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