A partir d'échantillons tumoraux prélevés sur 64 patientes atteintes d'un cancer du sein HER2+ en France, cette étude identifie, sur la base de données d'expression de gènes, quatre sous-groupes de la maladie exhibant des caractéristiques distinctes en termes de mutations somatiques, de changements du nombre de copies de gènes ou de variations structurales

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

Ferrari, Anthony ; Vincent-Salomon, Anne ; Pivot, Xavier ; Sertier, Anne-Sophie ; Thomas, Emilie ; Tonon, Laurie ; Boyault, Sandrine ; Mulugeta, Eskeatnaf ; Treilleux, Isabelle ; MacGrogan, Gaëtan ; Arnould, Laurent ; Kielbassa, Janice ; Le Texier, Vincent ; Blanche, Helene ; Deleuze, Jean-Francois ; Jacquemier, Jocelyne ; Mathieu, Marie-Christine ; Pénault-Llorca, Frédérique ; Bibeau, Frédéric ; Mariani, Odette ; Mannina, Cecile ; Pierga, Jean-Yves ; Tredan, Olivier ; Bachelot, Thomas ; Bonnefoi, Hervé ; Romieu, Gilles ; Fumoleau, Pierre ; Delaloge, Suzette ; Rios, Maria ; Ferrero, Jean-Marc ; Tarpin, Carole ; Bouteille, Catherine ; Calvo, Fabien ; Gut, Ivo Glynne ; Gut, Marta ; Martin, Sancha ; Nik-Zainal, Serena ; Stratton, Michael R. ; Pauporté, Iris ; Saintigny, Pierre ; Birnbaum, Daniel ; Viari, Alain ; Thomas, Gilles

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 [...]

A partir d'échantillons tumoraux prélevés sur 151 patients atteints d'un cancer de la tête et du cou récidivant et/ou métastatique, cette étude identifie un ensemble d'anomalies moléculaires susceptibles d'induire la prescription d'une thérapie ciblée

The molecular landscape of recurrent and metastatic head and neck cancers: Insights from a precision oncology sequencing platform

Morris, L. T. ; Chandramohan, R. ; West, L. ; et al.,

Importance  Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies. Objective  To illuminate the distinct biology of recurrent and [...]

Menée à l'aide de souris transgéniques, cette étude met en évidence le rôle joué par la protéine p53 dans la régulation de la réponse antitumorale des lymphocytes T

Lack of p53 Augments Anti-Tumor Functions In Cytolytic T Cells

Banerjee, Anirban ; Thyagarajan, Krishnamurthy ; Chatterjee, Shilpak ; Chakraborty, Paramita ; Kesarwani, Pravin ; Soloshchenko, Myroslawa ; Hommrani, Mazen Al ; Andrijauskaite, Kristina ; Moxley, Kelly ; Janakiraman, Harinarayanan ; Scheffel, Matthew J. ; Helke, Kristi ; Armeson, Kent ; Palanisamy, Viswanathan ; Rubinstein, Mark P. ; Garrett-Mayer, Elizabeth ; Cole, David J. ; Paulos, Chrystal M. ; Voelkel-Johnson, Christina ; Nishimura, Michael I. ; Mehrotra, Shikhar

Repetitive stimulation of T cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and anti-tumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS dependent JNK activation that leads to its activation induced cell death (AICD). Since tumor suppressor protein p53 is also a redox active [...]

Cet article passe en revue les travaux récents sur les mécanismes moléculaires liés au développement et à la progression d'une leucémie lymphoblastique aiguë T

The genetics and mechanisms of T cell acute lymphoblastic leukaemia

Belver, Laura ; Ferrando, Adolfo

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy derived from early T cell progenitors. In recent years genomic and transcriptomic studies have uncovered major oncogenic and tumour suppressor pathways involved in T-ALL transformation and identified distinct biological groups associated with prognosis. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and improved animal models of leukaemia and has opened [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par un complexe protéique (WASF3-NCKAP1-CYFIP1) dans le processus métastatique d'un cancer du sein, puis suggère une stratégie thérapeutique visant à déstabiliser ce complexe

The WASF3-NCKAP1-CYFIP1 complex is essential for breast cancer metastasis

Teng, Yong ; Qin, Haiyan ; Bahssan, Abdulaziz ; Bendzunas, George ; Kennedy, Eileen J. ; Cowell, John

Inactivation of the WASF3 gene suppresses invasion and metastasis of breast cancer cells. WASF3 function is regulated through a protein complex that includes the NCKAP1 and CYFIP1 proteins. Here we report that silencing NCKAP1 destabilizes the WASF3 complex, resulting in a suppression of the invasive capacity of breast, prostate and colon cancer cells. In an in vivo model of spontaneous metastasis in immunocompromized mice, loss of NCKAP1 also suppresses metastasis. Activation of the WASF [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la kinase Cdk5 favorise l'échappement immunitaire des cellules de médulloblastome

Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity

Dorand, R. Dixon ; Nthale, Joseph ; Myers, Jay T. ; Barkauskas, Deborah S. ; Avril, Stefanie ; Chirieleison, Steven M. ; Pareek, Tej K. ; Abbott, Derek W. ; Stearns, Duncan S. ; Letterio, John J. ; Huang, Alex Y. ; Petrosiute, Agne

Despite the dramatic success of cancer immunotherapy, many types of cancer do not respond. Understanding why could help us to find ways to enhance the overall responsiveness of tumors to immunotherapies. Dorand et al. report that cyclin-dependent kinase 5 (Cdk5), an enzyme that is highly expressed by neurons in many brain cancers, may dampen the ability of T cells to reject tumors. In a mouse model of medulloblastoma, if tumors were Cdk5 deficient, T cells were able to remove them. This [...]

Cet article passe en revue l'intérêt des technologies d'ingéniérie du génome, notamment la technologie CRISPR, pour mener des études fonctionnelles permettant de donner du sens à l'identification de mutations associées au cancer dans des études de séquençage

The present and future of genome editing in cancer research

Li, Xiaoyi ; Wu, Raymond ; Ventura, Andrea

The widespread use of high-throughput genome sequencing methods is profoundly changing the way we understand, classify, and treat human cancers. To make sense of the deluge of sequencing data generated in the clinic, more effective and rapid assessments of the functional relevance of newly discovered cancer-associated mutations are urgently needed. In this review, we discuss how genome editing technologies are responding to this major challenge. Largely focusing on CRISPR-based methods, we will [...]

Cet article présente un modèle, basé sur une approche évolutionniste, permettant de rendre compte du développement d'un adénocarcinome canalaire du pancréas

Pancreatic cancer biology and genetics from an evolutionary perspective

Makohon-Moore, Alvin ; Iacobuzio-Donahue, Christine A.

Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures [...]