Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients

Győrffy, Balázs; Lánczky, András; Szállási, Zoltán

doi:10.1530/erc-11-0329

Cited by 785 publications

(856 citation statements)

References 93 publications

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“…[38][39][40] Moreover, this is the first study delineating ICD-parameters based attractor-and convergent-metagenes. Overall, while both ICD-derived cancer type-specific as well as -independent consensus-metagenes were associated with significantly prolonged survival of cancer patients when highly expressed; yet it was the cancer type-independent consensus-metagene that had the best ability to act as attractor-metagene for stable convergentmetagenes with absolute coverage.…”

Section: Discussionmentioning

confidence: 91%

“…1). 40 To this end, the patients were first stratified into two groups on the basis of high or low expression of respective ICD-associated parameters (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…Based on above trends, in histological terms, it is worth considering that, breast cancer and ovarian cancers are mostly of adenocarcinoma (ADC) histological-type 39,40,42 whereas lung cancer can be relatively more strongly subdivided into ADC and squamous cell carcinoma (SCC) across patients. 38,42 Thus, we analyzed whether the respective metagene signatures show association with prolonged OS in both patients with lung-ADC or lung-SCC.…”

Section: Resultsmentioning

confidence: 99%

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Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis

2015

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The emerging role of the cancer cell-immune cell interface in shaping tumorigenesis/anticancer immunotherapy has increased the need to identify prognostic biomarkers. Henceforth, our primary aim was to identify the immunogenic cell death (ICD)-derived metagene signatures in breast, lung and ovarian cancer that associate with improved patient survival. To this end, we analyzed the prognostic impact of differential gene-expression of 33 pre-clinically-validated ICD-parameters through a large-scale metaanalysis involving 3,983 patients ('discovery' dataset) across lung (1,432), breast (1,115) and ovarian (1,436) malignancies. The main results were also substantiated in 'validation' datasets consisting of 818 patients of same cancer-types (i.e. 285 breast/274 lung/259 ovarian). The ICD-associated parameters exhibited a highly-clustered and largely cancer type-specific prognostic impact. Interestingly, we delineated ICDderived consensus-metagene signatures that exhibited a positive prognostic impact that was either cancer type-independent or specific. Importantly, most of these ICD-derived consensus-metagenes (acted as attractor-metagenes and thereby) 'attracted' highly co-expressing sets of genes or convergentmetagenes. These convergent-metagenes also exhibited positive prognostic impact in respective cancer types. Remarkably, we found that the cancer type-independent consensus-metagene acted as an 'attractor' for cancer-specific convergent-metagenes. This reaffirms that the immunological prognostic landscape of cancer tends to segregate between cancer-independent and cancer-type specific gene signatures. Moreover, this prognostic landscape was largely dominated by the classical T cell activity/ infiltration/function-related biomarkers. Interestingly, each cancer type tended to associate with biomarkers representing a specific T cell activity or function rather than pan-T cell biomarkers. Thus, our analysis confirms that ICD can serve as a platform for discovery of novel prognostic metagenes.

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Section: Discussionmentioning

confidence: 91%

“…1). 40 To this end, the patients were first stratified into two groups on the basis of high or low expression of respective ICD-associated parameters (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis

2015

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“… Overall survival of ER ‐negative metastatic breast cancer ( n = 226) (A) and lung adenocarcinoma ( n = 719) (B) patients according to MARK 4 mRNA levels found in their tumours was represented using the Kaplan–Meier plotter 25.A cDNA array for 24 matched lung cancers and surrounding normal tissue was analysed for MARK 4 expression. Expression levels from tumours were normalised to their respective normal control and the percentage of cases for the indicated fold expression in the tumour represented as a pie chart.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

miR‐515‐5p controls cancer cell migration throughMARK4 regulation

et al. 2016

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Here, we show that miR‐515‐5p inhibits cancer cell migration and metastasis. RNA‐seq analyses of both oestrogen receptor receptor‐positive and receptor‐negative breast cancer cells overexpressing miR‐515‐5p reveal down‐regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR‐515‐5p inhibits MARK4 directly 3′ UTR interaction and that MARK4 knock‐down mimics the effect of miR‐515‐5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR‐515‐5p, suggesting miR‐515‐5p mediates this process through MARK4 down‐regulation. Furthermore, miR‐515‐5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR‐515‐5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR‐515‐5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival, respectively. Taken together, these data demonstrate the importance of miR‐515‐5p/MARK4 regulation in cell migration and metastasis across two common cancers.

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Cell type‐selective pathways and clinical associations of lysophosphatidic acid biosynthesis and signaling in the ovarian cancer microenvironment

et al. 2018

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The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show that the levels of multiple acyl‐LPA species are strongly elevated in ascites versus plasma and are associated with short relapse‐free survival. Data derived from transcriptome and secretome analyses of primary ascite‐derived cells indicate that (a) the major route of LPA synthesis is the consecutive action of a secretory phospholipase A2 (PLA2) and autotaxin, (b) that the components of this pathway are coordinately upregulated in ascites, and (c) that CD163+CD206+ tumor‐associated macrophages play an essential role as main producers of PLA2G7 and autotaxin. The latter conclusion is consistent with mass spectrometry‐based metabolomic analyses of conditioned medium from ascites cells, which showed that tumor‐associated macrophages, but not tumor cells, are able to produce 20:4 acyl‐LPA in lipid‐free medium. Furthermore, our transcriptomic data revealed that LPA receptor (LPAR) genes are expressed in a clearly cell type‐selective manner: While tumor cells express predominantly LPAR1‐3, macrophages and T cells also express LPAR5 and LPAR6 at high levels, pointing to cell type‐selective LPA signaling pathways. RNA profiling identified cytokines linked to cell motility and migration as the most conspicuous class of LPA‐induced genes in macrophages, suggesting that LPA exerts protumorigenic properties at least in part via the tumor secretome.

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Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients

Cited by 785 publications

References 93 publications

Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis

Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis

miR‐515‐5p controls cancer cell migration throughMARK4 regulation

Cell type‐selective pathways and clinical associations of lysophosphatidic acid biosynthesis and signaling in the ovarian cancer microenvironment

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