Génomique

Publications

Année de publication : 2018

Houda Benhelli-Mokrani, Zeyni Mansuroglu, Alban Chauderlier, Benoit Albaud, David Gentien, Sabrina Sommer, Claire Schirmer, Lucie Laqueuvre, Thibaut Josse, Luc Buée, Bruno Lefebvre, Marie-Christine Galas, Sylvie Souès, Eliette Bonnefoy (2018 Oct 16)

Genome-wide identification of genic and intergenic neuronal DNA regions bound by Tau protein under physiological and stress conditions.

Nucleic acids research : DOI : 10.1093/nar/gky929 En savoir plus
Résumé

Tauopathies such as Alzheimer’s Disease (AD) are neurodegenerative disorders for which there is presently no cure. They are named after the abnormal oligomerization/aggregation of the neuronal microtubule-associated Tau protein. Besides its role as a microtubule-associated protein, a DNA-binding capacity and a nuclear localization for Tau protein has been described in neurons. While questioning the potential role of Tau-DNA binding in the development of tauopathies, we have carried out a large-scale analysis of the interaction of Tau protein with the neuronal genome under physiological and heat stress conditions using the ChIP-on-chip technique that combines Chromatin ImmunoPrecipitation (ChIP) with DNA microarray (chip). Our findings show that Tau protein specifically interacts with genic and intergenic DNA sequences of primary culture of neurons with a preference for DNA regions positioned beyond the ±5000 bp range from transcription start site. An AG-rich DNA motif was found recurrently present within Tau-interacting regions and 30% of Tau-interacting regions overlapped DNA sequences coding for lncRNAs. Neurological processes affected in AD were enriched among Tau-interacting regions with in vivo gene expression assays being indicative of a transcriptional repressor role for Tau protein, which was exacerbated in neurons displaying nuclear pathological oligomerized forms of Tau protein.

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P Cottu, V D'Hondt, S Dureau, F Lerebours, I Desmoulins, P-E Heudel, F P Duhoux, C Levy, M-A Mouret-Reynier, F Dalenc, J-S Frenel, C Jouannaud, L Venat-Bouvet, S Nguyen, J-M Ferrero, J-L Canon, J Grenier, C Callens, D Gentien, J Lemonnier, A Vincent-Salomon, S Delaloge (2018 Oct 12)

Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer.

Annals of oncology : official journal of the European Society for Medical Oncology : DOI : 10.1093/annonc/mdy448 En savoir plus
Résumé

Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC.

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Camille Tlemsani, Eric Pasmant, Pascaline Boudou-Rouquette, Audrey Bellesoeur, Julien Even, Frédérique Larousserie, Cécile Reyes, David Gentien, Jérôme Alexandre, Michel Vidaud, Philippe Anract, Karen Leroy, François Goldwasser (2018 Jul 26)

BRCA2 Loss-of-Function and High Sensitivity to Cisplatin-Based Chemotherapy in a Patient With a Pleomorphic Soft Tissue Sarcoma: Effect of Genomic Medicine.

The American journal of the medical sciences : DOI : S0002-9629(18)30174-5 En savoir plus
Résumé

We report the case of a patient with a BRCA2 germline mutation who developed a localized pleomorphic soft tissue sarcoma of the leg with poor prognostic features. BRCA2 germline mutations were not previously reported to be associated with pleomorphic sarcoma. BRCA2 loss-of-heterozygosity was found in the tumor, resulting in a complete BRCA2 loss-of-function. BRCA2 deficiency is associated with sensitivity to cisplatin-based chemotherapy in breast and ovarian cancer patients. We used a cisplatin-based chemotherapy. A rapid major partial response was obtained, which allowed a curative and conservative surgical resection of the sarcoma followed by adjuvant irradiation. This case illustrates that sarcoma patients may present unexpected but targetable genetic abnormalities and that BRCA2 loss-of-function may be targetable in sarcoma as it is associated with enhanced sensitivity to cisplatin. Our observation emphasizes the input of genomic medicine in clinical practice, its importance for treatment decisions, and the overlap between constitutional and somatic genetics.

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Sandrine Tury, Franck Assayag, Florian Bonin, Sophie Chateau-Joubert, Jean-Luc Servely, Sophie Vacher, Véronique Becette, Martial Caly, Audrey Rapinat, David Gentien, Pierre de la Grange, Anne Schnitzler, François Lallemand, Elisabetta Marangoni, Ivan Bièche, Céline Callens (2018 Jun 8)

The iron chelator deferasirox synergizes with chemotherapy to treat triple negative breast cancers.

The Journal of pathology : DOI : 10.1002/path.5104 En savoir plus
Résumé

To ensure their high proliferation rate, tumor cells display an iron metabolic disorder with increased iron needs, making them more susceptible to iron deprivation. This vulnerability could be a therapeutic target. In breast cancers, the development of new therapeutic approaches is urgently needed for patients with triple negative tumors which frequently relapse after chemotherapy and suffer from a lack of targeted therapies. In this work, we demonstrated that deferasirox (DFX) synergizes with standard chemotherapeutic agents such as with doxorubicin, cisplatin and carboplatin to inhibit cell proliferation and induce apoptosis and autophagy in triple-negative breast cancer (TNBC) cell lines. Moreover, the combination of DFX with doxorubicin and cyclophosphamide delayed recurrences in breast cancer patient-derived xenografts without increasing the side-effects of chemotherapies alone or altering global iron storage of mice. Antitumor synergy of DFX and doxorubicin seems to involve down-regulation of the PI3K and NF-κB pathways. Iron deprivation in combination with chemotherapy could thus help to improve the effectiveness of chemotherapy in TNBC patients without increasing toxicities. This article is protected by copyright. All rights reserved.

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