scholarly journals DNA methylation-based profiling reveals distinct clusters with survival heterogeneity in high-grade serous ovarian cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jieyu Wang ◽  
Jun Li ◽  
Ruifang Chen ◽  
Huiran Yue ◽  
Wenzhi Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Methylation ◽  
Proportional Hazards Model ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
The Cancer Genome Atlas ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Prognostic Information ◽  
Cpg Sites

AbstractHigh-grade serous ovarian cancer (HGSOC) is the most common type of epigenetically heterogeneous ovarian cancer. Methylation typing has previously been used in many tumour types but not in HGSOC. Methylation typing in HGSOC may promote the development of personalized care. The present study used DNA methylation data from The Cancer Genome Atlas database and identified four unique methylation subtypes of HGSOC. With the poorest prognosis and high frequency of residual tumours, cluster 4 featured hypermethylation of a panel of genes, which indicates that demethylation agents may be tested in this group and that neoadjuvant chemotherapy may be used to reduce the possibility of residual lesions. Cluster 1 and cluster 2 were significantly associated with metastasis genes and metabolic disorders, respectively. Two feature CpG sites, cg24673765 and cg25574024, were obtained through Cox proportional hazards model analysis of the CpG sites. Based on the methylation level of the two CpG sites, the samples were classified into high- and low-risk groups to identify the prognostic information. Similar results were obtained in the validation set. Taken together, these results explain the epigenetic heterogeneity of HGSOC and provide guidance to clinicians for the prognosis of HGSOC based on DNA methylation sites.

Proliferation-dominant high-grade astrocytoma: survival benefit associated with extensive resection of FLAIR abnormality region

2020 ◽  
Vol 132 (4) ◽  
pp. 998-1005 ◽  
Author(s):  
Haihui Jiang ◽  
Yong Cui ◽  
Xiang Liu ◽  
Xiaohui Ren ◽  
Mingxiao Li ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Characteristic Curve ◽  
Extent Of Resection ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
High Grade ◽  
Extensive Resection ◽  
High Grade Astrocytoma

OBJECTIVEThe aim of this study was to investigate the relationship between extent of resection (EOR) and survival in terms of clinical, molecular, and radiological factors in high-grade astrocytoma (HGA).METHODSClinical and radiological data from 585 cases of molecularly defined HGA were reviewed. In each case, the EOR was evaluated twice: once according to contrast-enhanced T1-weighted images (CE-T1WI) and once according to fluid attenuated inversion recovery (FLAIR) images. The ratio of the volume of the region of abnormality in CE-T1WI to that in FLAIR images (VFLAIR/VCE-T1WI) was calculated and a receiver operating characteristic curve was used to determine the optimal cutoff value for that ratio. Univariate and multivariate analyses were performed to identify the prognostic value of each factor.RESULTSBoth the EOR evaluated from CE-T1WI and the EOR evaluated from FLAIR could divide the whole cohort into 4 subgroups with different survival outcomes (p < 0.001). Cases were stratified into 2 subtypes based on VFLAIR/VCE-T1WIwith a cutoff of 10: a proliferation-dominant subtype and a diffusion-dominant subtype. Kaplan-Meier analysis showed a significant survival advantage for the proliferation-dominant subtype (p < 0.0001). The prognostic implication has been further confirmed in the Cox proportional hazards model (HR 1.105, 95% CI 1.078–1.134, p < 0.0001). The survival of patients with proliferation-dominant HGA was significantly prolonged in association with extensive resection of the FLAIR abnormality region beyond contrast-enhancing tumor (p = 0.03), while no survival benefit was observed in association with the extensive resection in the diffusion-dominant subtype (p=0.86).CONCLUSIONSVFLAIR/VCE-T1WIis an important classifier that could divide the HGA into 2 subtypes with distinct invasive features. Patients with proliferation-dominant HGA can benefit from extensive resection of the FLAIR abnormality region, which provides the theoretical basis for a personalized resection strategy.

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.

Abstract 3154: Cell-free circulating tumor DNA methylation in high-grade serous ovarian cancer

2016 ◽  
Author(s):  
Kayleigh R. Davis ◽  
Kirsty J. Flower ◽  
Jane V. Borley ◽  
Charlotte SM Wilhelm-Benartzi ◽  
Robert Brown
Keyword(s):  
Ovarian Cancer ◽  
Dna Methylation ◽  
Circulating Tumor Dna ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Tumor Dna

Mucin O-glycosylating enzyme GALNT2 facilitates the malignant character of glioma by activating the EGFR/PI3K/Akt/mTOR axis

2019 ◽  
Vol 133 (10) ◽  
pp. 1167-1184 ◽  
Author(s):  
Zhongzheng Sun ◽  
Hao Xue ◽  
Yan Wei ◽  
Chaochao Wang ◽  
Rui Yu ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Glioma Cell ◽  
Proportional Hazards Model ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
The Cancer Genome Atlas ◽  
Matrix Metalloproteinase 2 ◽  
Migration And Invasion ◽  
Expression Levels

AbstractN-Acetylgalactosaminyltransferase 2 (GALNT2), the enzyme that regulates the initial step of mucin O-glycosylation, has been reported to play a role in influencing the malignancy of various cancers. However, the mechanism through which it influences gliomas is still unknown. In the current study, the Cox proportional hazards model was used to select genes. Data obtained from The Cancer Genome Atlas (TCGA) database and immunohistochemistry (IHC) of clinical specimens showed that increased GALNT2 expression levels were associated with an unfavorable prognosis and a higher tumor grade in human gliomas. Then, GALNT2 knockdown and overexpression were performed in glioma cell lines and verified by quantitative real-time PCR (qRT-PCR) and Western blotting. Functional assays demonstrated that GALNT2 was closely related to glioma cell proliferation, cycle transition, migration and invasion. Western blot analysis and lectin pull-down assays indicated that GALNT2 knockdown decreased the level of phosphorylated epidermal growth factor receptor (EGFR) and the expression of the Tn antigen on EGFR and affected the expression levels of p21, cyclin-dependent kinase 4 (CDK4), cyclinD1, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) through the EGFR/PI3K/Akt/mTOR pathway. GALNT2 overexpression had the opposite effects. In vivo, the growth of orthotopic glioma xenografts in nude mice was distinctly inhibited by the expression of GALNT2 shRNA, and the tumors with GALNT2 shRNA exhibited less aggressiveness and reduced expression of Ki67 and MMP2. Overall, GALNT2 facilitates the malignant characteristics of glioma by influencing the O-glycosylation and phosphorylation of EGFR and the subsequent downstream PI3K/Akt/mTOR axis. Therefore, GALNT2 may serve as a novel biomarker and a potential target for future therapy of glioma.

scholarly journals Immune Modeling Analysis Reveals Immunologic Signatures Associated With Improved Outcomes in High Grade Serous Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Nicole E. James ◽  
Katherine Miller ◽  
Natalie LaFranzo ◽  
Erin Lips ◽  
Morgan Woodman ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Cell ◽  
Immune Escape ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Immunological Responses ◽  
Modeling Analysis ◽  
Immune Cell Subsets

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide, as patients are typically diagnosed at a late stage and eventually develop chemoresistant disease following front-line platinum-taxane based therapy. Only modest results have been achieved with PD-1 based immunotherapy in ovarian cancer patients, despite the fact that immunological responses are observed in EOC patients. Therefore, the goal of this present study was to identify novel immune response genes and cell subsets significantly associated with improved high grade serous ovarian cancer (HGSOC) patient prognosis. A transcriptomic-based immune modeling analysis was employed to determine levels of 8 immune cell subsets, 10 immune escape genes, and 22 co-inhibitory/co-stimulatory molecules in 26 HGSOC tumors. Multidimensional immune profiling analysis revealed CTLA-4, LAG-3, and Tregs as predictive for improved progression-free survival (PFS). Furthermore, the co-stimulatory receptor ICOS was also found to be significantly increased in patients with a longer PFS and positively correlated with levels of CTLA-4, PD-1, and infiltration of immune cell subsets. Both ICOS and LAG-3 were found to be significantly associated with improved overall survival in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Finally, PVRL2 was identified as the most highly expressed transcript in our analysis, with immunohistochemistry results confirming its overexpression in HGSOC samples compared to normal/benign. Results were corroborated by parallel analyses of TCGA data. Overall, this multidimensional immune modeling analysis uncovers important prognostic immune factors that improve our understanding of the unique immune microenvironment of ovarian cancer.

scholarly journals Focal Recurrent Copy Number Alterations Characterize Disease Relapse in High Grade Serous Ovarian Cancer Patients with Good Clinical Prognosis: A Pilot Study

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 678 ◽  
Author(s):  
Dugo ◽  
Devecchi ◽  
De Cecco ◽  
Cecchin ◽  
Mezzanzanica ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Molecular Heterogeneity ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Disease Relapse ◽  
Clinical Prognosis ◽  
Primary Surgery ◽  
Altered Gene

High grade serous ovarian cancer (HGSOC) retains high molecular heterogeneity and genomic instability, which currently limit the treatment opportunities. HGSOC patients receiving complete cytoreduction (R0) at primary surgery and platinum-based therapy may unevenly experience early disease relapse, in spite of their clinically favorable prognosis. To identify distinctive traits of the genomic landscape guiding tumor progression, we focused on the R0 patients of The Cancer Genome Atlas (TCGA) ovarian serous cystadenocarcinoma (TCGA-OV) dataset and classified them according to their time to relapse (TTR) from surgery. We included in the study two groups of R0-TCGA patients experiencing substantially different outcome: Resistant (R; TTR ≤ 12 months; n = 11) and frankly Sensitive (fS; TTR ≥ 24 months; n = 16). We performed an integrated clinical, RNA-Sequencing, exome and somatic copy number alteration (sCNA) data analysis. No significant differences in mutational landscape were detected, although the lack of BRCA-related mutational signature characterized the R group. Focal sCNA analysis showed a higher frequency of amplification in R group and deletions in fS group respectively, involving cytobands not commonly detected by recurrent sCNA analysis. Functional analysis of focal sCNA with a concordantly altered gene expression identified in R group a gain in Notch, and interferon signaling and fatty acid metabolism. We are aware of the constraints related to the low number of OC cases analyzed. It is worth noting, however, that the sCNA identified in this exploratory analysis and characterizing Pt-resistance are novel, deserving validation in a wider cohort of patients achieving complete surgical debulking.

Serum IGFBP4 levels in combination with miliary disease: A candidate predictor of ovarian cancer progression-free survival.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5079-5079
Author(s):  
Samantha Cohen
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Residual Disease ◽  
Statistical Significance ◽  
Serum Levels ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Separate Analysis

5079 Background: Insulin-like growth factor binding protein, IGFBP4, was shown to be highly expressed across all stages of epithelial ovarian cancer (EOC) and serum levels are elevated in EOC. Moreover, IGFBP4 levels are ~3x greater in women with malignant pelvic masses. We investigated whether ascites volume and the presence of miliary disease in combination with serum levels of IGFBP4 are independent predictors of survival. Methods: A prospective and retrospective analysis was performed. Patients were enrolled at the time of cytoreductive surgery. Ascites volume was either absent, <500 cc (low), or >= 500 cc (high), and the presence of miliary disease was recorded. The IGFBP4 cutoff was 1064.5 ug/ml based upon previous results. The Kaplan-Meier product limit method was used to estimate PFS probabilities. The Cox proportional hazards model was used to estimate hazard ratios (HR) and corresponding 95% CI. Results: 57 cases were included in the analysis of ascites volume and miliary disease. Cytoreductive outcomes were complete gross resection (44.8%), optimal (<=1cm residual disease; 44.8%), and suboptimal ( >1cm residual disease; 10.3%). Histologic subtypes: papillary serous (n=35; 61.4%), mucinous (n=15; 26.3%), endometrioid (n=4; 7.0%), and clear cell (n=3; 5.3%). Stage distribution was 21.1% I/II, and 78.9% III/IV. PFS was unaffected by ascites volume (p=0.341) or miliary disease. Among this cohort, 29 had IGFBP4 levels available for a separate analysis. Patients with high IGFBP4 and miliary disease were 5.5 times as likely to recur compared with patients with miliary disease and low IGFBP4 (HR=5.55 [0.77, 39.82]), and the statistical significance was borderline (p<0.088). No statistically significant differences were detected between rates of recurrence among patients with high and low IGFBP4 values in combination with ascites volume. Conclusions: These exploratory studies suggest that patients with high IGFBP4 serum levels and miliary disease were > 5 times as likely to recur compared to women with miliary disease and low IGFBP4 levels. Future studies examining these variables using a larger population and examining the biologic basis of this relationship are planned.

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