Histone variants: critical determinants in tumour heterogeneity

International audienceMalignant cell transformation could be considered as a series of cell reprogramming events driven by oncogenic transcription factors and upstream signalling pathways. Chromatin plasticity and dynamics are critical determinants in the control of cell reprograming. An increase in chromatin dynamics could therefore constitute an essential step in driving oncogenesis and in generating tumour cell heterogeneity, which is indispensable for the selection of aggressive properties, including the ability of cells to disseminate and acquire resistance to treatments. Histone supply and dosage, as well as histone variants, are the best-known regulators of chromatin dynamics. By facilitating cell reprogramming, histone under-dosage and histone variants should also be crucial in cell transformation and tumour metastasis. Here we summarize and discuss our knowledge of the role of histone supply and histone variants in chromatin dynamics and their ability to enhance oncogenic cell reprogramming and tumour heterogeneity

Aberrant activation of five embryonic stem cell-specific genes robustly predicts a high risk of relapse in breast cancers

Abstract Background In breast cancer, as in all cancers, genetic and epigenetic deregulations can result in out-of-context expressions of a set of normally silent tissue-specific genes. The activation of some of these genes in various cancers empowers tumours cells with new properties and drives enhanced proliferation and metastatic activity, leading to a poor survival prognosis. Results In this work, we undertook an unprecedented systematic and unbiased analysis of out-of-context activations of a specific set of tissue-specific genes from testis, placenta and embryonic stem cells, not expressed in normal breast tissue as a source of novel prognostic biomarkers. To this end, we combined a strict machine learning framework of transcriptomic data analysis, and successfully created a new robust tool, validated in several independent datasets, which is able to identify patients with a high risk of relapse. This unbiased approach allowed us to identify a panel of five biomarkers, DNMT3B, EXO1, MCM10, CENPF and CENPE, that are robustly and significantly associated with disease-free survival prognosis in breast cancer. Based on these findings, we created a new Gene Expression Classifier (GEC) that stratifies patients. Additionally, thanks to the identified GEC, we were able to paint the specific molecular portraits of the particularly aggressive tumours, which show characteristics of male germ cells, with a particular metabolic gene signature, associated with an enrichment in pro-metastatic and pro-proliferation gene expression. Conclusions The GEC classifier is able to reliably identify patients with a high risk of relapse at early stages of the disease. We especially recommend to use the GEC tool for patients with the luminal-A molecular subtype of breast cancer, generally considered of a favourable disease-free survival prognosis, to detect the fraction of patients undergoing a high risk of relapse

Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

International audienceT-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of TALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on TALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of TALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients

The combined detection of Amphiregulin, Cyclin A1 and DDX20/Gemin3 expression predicts aggressive forms of oral squamous cell carcinoma

International audienceBACKGROUND: Large-scale genetic and epigenetic deregulations enable cancer cells to ectopically activate tissue-specific expression programmes. A specifically designed strategy was applied to oral squamous cell carcinomas (OSCC) in order to detect ectopic gene activations and develop a prognostic stratification test. METHODS: A dedicated original prognosis biomarker discovery approach was implemented using genome-wide transcriptomic data of OSCC, including training and validation cohorts. Abnormal expressions of silent genes were systematically detected, correlated with survival probabilities and evaluated as predictive biomarkers. The resulting stratification test was confirmed in an independent cohort using immunohistochemistry. RESULTS: A specific gene expression signature, including a combination of three genes, AREG, CCNA1 and DDX20, was found associated with high-risk OSCC in univariate and multivariate analyses. It was translated into an immunohistochemistry-based test, which successfully stratified patients of our own independent cohort. DISCUSSION: The exploration of the whole gene expression profile characterising aggressive OSCC tumours highlights their enhanced proliferative and poorly differentiated intrinsic nature. Experimental targeting of CCNA1 in OSCC cells is associated with a shift of transcriptomic signature towards the less aggressive form of OSCC, suggesting that CCNA1 could be a good target for therapeutic approaches

Additional file 2 of Aberrant activation of five embryonic stem cell-specific genes robustly predicts a high risk of relapse in breast cancers

Additional file 2: Table S1. List of genes with predominant expression in testis, placenta and/or embryonic stem cells. Table S2. Frequencies of ectopic activations of the tissue-specific genes. Table S3. Results of the validation step in the biomarker discovery pipeline. Table S4. Datasets of normal tissues and breast cancers with corresponding sample sizes. Table S5. List of normal tissues and the corresponding sample sizes

Pregnancy exposure to synthetic phenols and placental DNA methylation -An epigenome-wide association study in male infants from the EDEN cohort ☆

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Additional file 1 of Aberrant activation of five embryonic stem cell-specific genes robustly predicts a high risk of relapse in breast cancers

Additional file 1: Fig. S1. (A) Heatmap showing the expression of 1882 genes in normal adult tissues with predominant expression in testis (male germinal), embryonic stem cells (ES cells) or placenta, and not expressed in normal breast (female genital). The expression levels of all genes are normalized by scaling each feature to a range between zero and one. The genes are ordered according their normalized expression levels in the tissues of interest (testis, placenta and ES cells, respectively). (B) Venn diagram showing the distribution of 1882 genes according the tissue of predominance: testis, embryonic stem cells and/or placenta. Fig. S2. Flow chart representing the main steps of the biomarker discovery pipeline. Fig. S3. Expression profiles in normal tissues of the five genes in the GEC panel DNMT3B, EXO1, MCM10, CENPF and CENPE based on RNA-seq data from GTEX and NCBI Sequence Read Archive. All five genes have a predominant expression profile in embryonic stem cells. They are also expressed in testis (male germinal) at lower levels. These genes are not expressed in normal breast and female genital tissues. Fig. S4. Kaplan-Meier individual survival curves of the genes DNMT3B, EXO1, MCM10, CENPF and CENPE in the training (TCGA-BRCA) and validation (GSE25066, GSE21653, GSE42568) datasets