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BACKGROUND. The tumor immune response is increasingly associated with better clinical outcomes in breast and other cancers. However, the evaluation of tumor-infiltrating lymphocytes (TILs) relies on histopathological measurements with limited accuracy and reproducibility. Here, we profiled DNA methylation markers to identify a methylation of TIL (MeTIL) signature that recapitulates TIL evaluations and their prognostic value for long-term outcomes in breast cancer (BC). METHODS. MeTIL signature scores were correlated with clinical endpoints reflecting overall or disease-free survival and a pathologic complete response to preoperative anthracycline therapy in 3 BC cohorts from the Jules Bordet Institute in Brussels and in other cancer types from The Cancer Genome Atlas. RESULTS. The MeTIL signature measured TIL distributions in a sensitive manner and predicted survival and response to chemotherapy in BC better than did histopathological assessment of TILs or gene expression-based immune markers, respectively. The MeTIL signature also improved the prediction of survival in other malignancies, including melanoma and lung cancer. Furthermore, the MeTIL signature predicted differences in survival for malignancies in which TILs were not known to have a prognostic value. Finally, we showed that MeTIL markers can be determined by bisulfite pyrosequencing of small amounts of DNA from formalin-fixed, paraffin-embedded tumor tissue, supporting clinical applications for this methodology. CONCLUSIONS. This study highlights the power of DNA methylation to evaluate tumor immune responses and the potential of this approach to improve the diagnosis and treatment of breast and other cancers. FUNDING. This work was funded by the Fonds National de la Recherche Scientifique (FNRS) and Televie, the INNOVIRIS Brussels Region BRUBREAST Project, the IUAP P7/03 program, the Belgian 'Foundation against Cancer,' the Breast Cancer Research Foundation (BCRF), and the Fonds Gaston Ithier., Introduction Breast cancer (BC) remains challenging to treat because of its vast heterogeneous nature. Even within BC subtypes, patients experience different rates of survival and responses to anticancer therapies. This [...]

Here, in a mouse model of skin squamous cell carcinoma, a key role is demonstrated for the transcription factor SOX2 in the initiation and progression of skin tumours. SOX2 involved in skin cancer In a mouse model of skin carcinogenesis, Cédric Blanpain and colleagues demonstrate a key role for the transcription factor SOX2 in initiation and progression of skin tumours. SOX2 is not expressed in normal skin, but it appears at an early stage in tumour formation. Tumour initiation can be prevented by deletion of the Sox2 gene. In addition, SOX2-expressing cells function as tumour propagating cells upon transplantation, while the removal of SOX2-postive cells from established tumours leads to regression. SOX2 appears to be able to contribute to both tumour initiation and progression by directly regulating genes involved in cancer functions such as stemness, proliferation, survival and invasion. Cancer stem cells (CSCs) have been reported in various cancers, including in skin squamous-cell carcinoma (SCC).sup.1,2,3,4. The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here we find that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells.sup.5,6, was the most upregulated transcription factor in the CSCs of squamous skin tumours in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours, and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which SOX2 is frequently genetically amplified.sup.7, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumour formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (SOX2-GFP knock-in mice), we showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumour-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of SOX2-expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to tumour regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC functions. Transcriptional profiling of SOX2-GFP-expressing CSCs and of tumour epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion and paraneoplastic syndrome. We demonstrate that SOX2, by marking and regulating the functions of skin tumour-initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours., Author(s): Soufiane Boumahdi [sup.1] , Gregory Driessens [sup.1] , Gaelle Lapouge [sup.1] , Sandrine Rorive [sup.2] [sup.3] , Dany Nassar [sup.1] , Marie Le Mercier [sup.2] , Benjamin Delatte [sup.4] [...]

Author(s): Emmanuelle Viré [1]; Carmen Brenner [1]; Rachel Deplus [1]; Loïc Blanchon [1]; Mario Fraga [2]; Céline Didelot [1]; Lluis Morey [3]; Aleyde Van Eynde [4]; David Bernard [1]; Jean-Marie [...]

Research demonstrates that EMSY protein binds BRCA2 within exon 3 region, which is deleted in cancer. It can silence the activation potential of BRCA2 exon 3 and is localized to sites of repair, following DNA damage, on chromosome 11q13.5 involved in breast and ovarian cancer. Furthermore, EMSY gene is amplified in sporadic breast cancer and advanced ovarian cancer.

What a difference time makes! It does not seem long since I learned, as a university student and as if it was a closed topic, that the regulation of fruitflies' [...]

Author(s): Emmanuelle Viré; Carmen Brenner; Rachel Deplus; Loïc Blanchon; Mario Fraga; Céline Didelot; Lluis Morey; Aleyde Van Eynde; David Bernard; Jean-Marie Vanderwinden; Mathieu Bollen; Manel Esteller; Luciano Di Croce; Yvan [...]

An abstract of the article "MBD3, a Component of the NuRD Complex, Facilitates Chromatin Alteration and Deposition of Epigenetic Marks," by Lluis Morey, Carmen Brenner, Raffaella Villa, Arantxa Gutierrez, Marcus Buschbeck, Clara Nervi, Saverio Minucci, Francois Fuks, and Francesco Fazi is presented.

DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. The molecular mechanisms underlying the specificity of methylation are unknown. We report here that the leukemia-promoting PML-RAR fusion protein induces gene hypermethylation and silencing by recruiting DNA methyltransferases to target promoters and that hypermethylation contributes to its leukemogenic potential Retinoic acid treatment induces promoter demethylation, gene reexpression, and reversion of the transformed phenotype. These results establish a mechanistic link between genetic and epigenetic changes during transformation and suggest that hypermethylation contributes to the early steps of carcinogenesis. [ABSTRACT FROM AUTHOR]

DNA methylation plays an important role in mammalian development and correlates with chromatin-associated gene silencing. The recruitment of MeCP2 to methylated CpG dinucleotides represents a major mechanism by which DNA methylation can repress transcription. MeCP2 silences gene expression partly by recruiting histone deacetylase (HDAC) activity, resulting in chromatin remodeling. Here, we show that MeCP2 associates with histone methyltransferase activity in vivo and that this activity is directed against Lys(9) of histone H3. Two characterized repression domains of MeCP2 are involved in tethering the histone methyltransferase to MeCP2. We asked if MeCP2 can deliver Lys(9) H3 methylation to the H19 gene, whose activity it represses. We show that the presence of MeCP2 on nucleosomes within the repressor region of the H19 gene (the differentially methylated domain) coincides with an increase in H3 Lys(9) methylation. Our data provide evidence that MeCP2 reinforces a repressive chromatin state by acting as a bridge between two global epigenetic modifications, DNA methylation and histone methylation.