Menée sur 156 patients atteints d'une leucémie lymphocytaire chronique, cette étude met en évidence l'effet des traitements sur l'évolution d'anomalies génomiques, notamment d'anomalies du nombre de copies de gènes

Clonal evolution, genomic drivers and effects of therapy in chronic lymphocytic leukemia

Ouillette, Peter ; Saiya-Cork, Kamlai ; Seymour, Erlene K. ; Li, Cheng ; Shedden, Kerby ; Malek, Sami N.

Purpose: The identification of gene mutations and structural genomic aberrations that are critically involved in CLL pathogenesis is still evolving. One may postulate that genomic driver lesions with effects on CLL cell proliferation, apoptosis thresholds or chemotherapy resistance should increase in frequency over time when measured sequentially in a CLL cohort. Experimental Design: We sequentially sampled a large well-characterized CLL cohort at a mean of 4 years between samplings and [...]

Menée sur des lignées cellulaires de lymphome hodgkinien, cette étude met en évidence des réarrangements chromosomiques massifs (phénomène de chromothripsis), dont certains sont associés à une résistance au dasatinib

Chromothripsis in Hodgkin lymphoma

Nagel, Stefan ; Meyer, Corinna ; Quentmeier, Hilmar ; Kaufmann, Maren ; Drexler, Hans G. ; MacLeod, Roderick A. F.

Chromosomal rearrangements are common features of most cancers, where they contribute to deregulated gene expression. Chromothripsis is a recently described oncogenic mechanism whereby small genomic pieces originating from one chromosomal region undergo massive rearrangements in a single step. Here, we document chromothripsis in Hodgkin lymphoma (HL) cell lines by genomic profiling, showing alternating amplicons of defined chromosomal regions. In L-1236 cells, fluorescent in situ hybridization [...]

Menée à l'aide d'une technique de séquençage de prochaine génération sur 15 patients atteints d'un cancer métastatique du poumon non à petites cellules, cette étude compare les anomalies génomiques dans les tumeurs primitives et les métastases

Next-Generation Sequencing Reveals High Concordance of Recurrent Somatic Alterations Between Primary Tumor and Metastases From Patients With Non–Small-Cell Lung Cancer

Vignot, Stéphane ; Frampton, Garrett M. ; Soria, Jean-Charles ; Yelensky, Roman ; Commo, Frederic ; Brambilla, Christian ; Palmer, Gary ; Moro-Sibilot, Denis ; Ross, Jeffrey S. ; Cronin, Maureen T. ; Andre, Fabrice ; Stephens, Philip J. ; Lazar, Vladimir ; Miller, Vincent A. ; Brambilla, Elisabeth

Purpose Characterization of the genomic changes that drive an individual patient’s disease is critical in management of many cancers. In patients with non–small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases. Patients and Methods Primary [...]

Menée sur des échantillons de tissu tumoral et de tissu sain prélevés sur 57 patients atteints d'un cancer de la prostate, cette étude met en évidence un phénomène de "chromoplexie", c'est-à-dire de translocations et de délétions interdépendantes induisant une dérégulation coordonnée de multiples gènes

Punctuated Evolution of Prostate Cancer Genomes

Baca, Sylvan C ; Prandi, Davide ; Lawrence, Michael S ; Mosquera, Juan Miguel ; Romanel, Alessandro ; Drier, Yotam ; Park, Kyung ; Kitabayashi, Naoki ; MacDonald, Theresa Y ; Ghandi, Mahmoud ; Van Allen, Eliezer ; Kryukov, Gregory V ; Sboner, Andrea ; Theurillat, Jean-Philippe ; Soong, T.  David ; Nickerson, Elizabeth ; Auclair, Daniel ; Tewari, Ashutosh ; Beltran, Himisha ; Onofrio, Robert C ; Boysen, Gunther ; Guiducci, Candace ; Barbieri, Christopher E ; Cibulskis, Kristian ; Sivachenko, Andrey ; Carter, Scott L ; Saksena, Gordon ; Voet, Douglas ; Ramos, Alex H ; Winckler, Wendy ; Cipicchio, Michelle ; Ardlie, Kristin ; Kantoff, Philip W ; Berger, Michael F ; Gabriel, Stacey B ; Golub, Todd R ; Meyerson, Matthew ; Lander, Eric S ; Elemento, Olivier ; Getz, Gad ; Demichelis, Francesca ; Rubin, Mark A ; Garraway, Levi A

The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly [...]

Menée sur 44 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un gliome diffus de bas grade, cette étude identifie de fréquents réarrangements du gène d'un facteur de transcription, MYBL1

Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1

Ramkissoon, Lori A. ; Horowitz, Peleg M. ; Craig, Justin M. ; Ramkissoon, Shakti H. ; Rich, Benjamin E. ; Schumacher, Steven E. ; McKenna, Aaron ; Lawrence, Michael S. ; Bergthold, Guillaume ; Brastianos, Priscilla K. ; Tabak, Barbara ; Ducar, Matthew D. ; Van Hummelen, Paul ; MacConaill, Laura E. ; Pouissant-Young, Tina ; Cho, Yoon-Jae ; Taha, Hala ; Mahmoud, Madeha ; Bowers, Daniel C. ; Margraf, Linda ; Tabori, Uri ; Hawkins, Cynthia ; Packer, Roger J. ; Hill, D. Ashley ; Pomeroy, Scott L. ; Eberhart, Charles G. ; Dunn, Ian F. ; Goumnerova, Liliana ; Getz, Gad ; Chan, Jennifer A. ; Santagata, Sandro ; Hahn, William C. ; Stiles, Charles D. ; Ligon, Azra H. ; Kieran, Mark W. ; Beroukhim, Rameen ; Ligon, Keith L.

Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited [...]

Menée sur des échantillons tumoraux prélevés sur 373 patientes atteintes d'un carcinome de l'endomètre, cette étude du projet "The Cancer Genome Atlas" montre que ces cancers peuvent être classés en quatre catégories sur la base de leurs anomalies génomiques

Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ~25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, [...]

Menée sur des échantillons tumoraux prélevés sur 38 patients atteints d'un carcinome épidermoïde de la bouche, cette étude identifie de fréquentes anomalies génomiques, notamment dans la voie de signalisation Notch

Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers

Pickering, Curtis R ; Zhang, Jiexin ; Yoo, Suk-Young ; Bengtsson, Linnea ; Moorthy, Shhyam ; Neskey, David M ; Zhao, Mei ; Ortega Alves, Marcus V ; Chang, Kyle ; Drummond, Jennifer ; Cortez, Elsa ; Xie, Tong-xin ; Zhang, Di ; Chung, Woonbok ; Issa, Jean-Pierre J ; Zweidler-McKay, Patrick A ; Wu, Xifeng ; El-Naggar, Adel K ; Weinstein, John N ; Wang, Jing ; Muzny, Donna M ; Gibbs, Richard A ; Wheeler, David A ; Myers, Jeffrey N ; Frederick, Mitchell J

The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we performed comprehensive genomic analysis of gene expression, copy number, methylation and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and two [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme mitochondrial par lequel la protéine du rétinoblastome induit une apoptose

The retinoblastoma protein induces apoptosis directly at the mitochondria

Hilgendorf, Keren I. ; Leshchiner, Elizaveta S. ; Nedelcu, Simona ; Maynard, Mindy A. ; Calo, Eliezer ; Ianari, Alessandra ; Walensky, Loren D. ; Lees, Jacqueline A.

The retinoblastoma protein gene RB-1 is mutated in one-third of human tumors. Its protein product, pRB (retinoblastoma protein), functions as a transcriptional coregulator in many fundamental cellular processes. Here, we report a nonnuclear role for pRB in apoptosis induction via pRB's direct participation in mitochondrial apoptosis. We uncovered this activity by finding that pRB potentiated TNFα-induced apoptosis even when translation was blocked. This proapoptotic function was highly [...]

Menée in vitro et sur des échantillons de cancer du sein et de mélanome, cette étude met en évidence un mécanisme par lequel, en régulant la sénescence cellulaire, la protéine Notch3 joue un role de suppresseur de tumeurs

Notch3 functions as a tumor suppressor by controlling cellular senescence

Cui, Hang ; Kong, Yahui ; Xu, Mei ; Zhang, Hong

Notch signaling regulates a broad spectrum of cell fate decisions and differentiation. Both oncogenic and tumor suppressor functions have been demonstrated for Notch signaling. However, little is known about the underlying mechanisms of its tumor suppressor function. Here we report that expression of Notch3, a member of Notch family transmembrane receptors, was elevated in human cells during senescence activated by various senescence-inducing stimuli. This up-regulation of Notch3 was required [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en induisant l'expression du gène SOCS3, le facteur de transcription PPARγ inhibe la croissance tumorale alimentée par l'interleukine 17

SOCS3 transactivation by PPARγ prevents IL-17-driven cancer growth

Berger, Helene ; Vegran, Frederique ; Chikh, Madijd ; Gilardi, Federica ; Ladoire, Sylvain ; Bugaut, Helene ; Mignot, Grégoire ; Chalmin, Fanny ; Bruchard, Melanie ; Derangere, Valentin ; Chevriaux, Angelique ; Rebe, Cedric ; Ryffel, Bernhard ; Pot, Caroline ; Hichami, Aziz ; Desvergne, Beatrice ; Ghiringhelli, François ; Apetoh, Lionel

Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here we identify the adapter encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory Th17 cells. Accordingly, [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la ribonucléase T2 dans le microenvironnement d'une tumeur de l'ovaire

Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis

Acquati, Francesco ; Lualdi, Marta ; Bertilaccio, Sabrina ; Monti, Laura ; Turconi, Giovanna ; Fabbri, Marco ; Grimaldi, Annalisa ; Anselmo, Achille ; Inforzato, Antonio ; Collotta, Angelo ; Cimetti, Laura ; Riva, Cristina ; Gribaldo, Laura ; Ghia, Paolo ; Taramelli, Roberto

In recent years, the role played by the stromal microenvironment has been given growing attention in order to achieve a full understanding of cancer initiation and progression. Because cancer is a tissue-based disease, the integrity of tissue architecture is a major constraint toward cancer growth. Indeed, a large contribution of the natural resistance to cancer stems from stromal microenvironment components, the dysregulation of which can facilitate cancer occurrence. For instance, recent [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la protéine RANKL dans la régulation des niveaux de progestérone et le développement d'un cancer du sein

Progesterone/RANKL Is a Major Regulatory Axis in the Human Breast

Tanos, Tamara ; Sflomos, George ; Echeverria, Pablo C. ; Ayyanan, Ayyakkannu ; Gutierrez, Maria ; Delaloye, Jean-Francois ; Raffoul, Wassim ; Fiche, Maryse ; Dougall, William ; Schneider, Pascal ; Yalcin-Ozuysal, Ozden ; Brisken, Cathrin

Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor κB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en induisant l'expression de la thrombospondine 1 dans des cellules myéloïdes GR1+ dérivées de la moelle osseuse, des cellules tumorales favorisent, dans des organes distants, un micro-environnement suppresseur de métastases

Bone Marrow-Derived Gr1+ Cells Can Generate a Metastasis-Resistant Microenvironment Via Induced Secretion of Thrombospondin-1

Catena, Raul ; Bhattacharya, Nandita ; Rayes, Tina El ; Wang, Suming ; Choi, Hyejin ; Gao, Dingcheng ; Ryu, Seongho ; Joshi, Natasha ; Bielenberg, Diane ; Lee, Sharrell B. ; Haukaas, Svein A. ; Gravdal, Karsten ; Halvorsen, Ole J. ; Akslen, Lars A. ; Watnick, Randolph S. ; Mittal, Vivek

Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en activant HIF-1α, une hypoxie tumorale favorise la formation de tissus fibreux dans le micro-environnement d'une tumeur du pancréas et, ainsi, rend les tumeurs plus agressives et plus résistantes aux traitements

Hypoxia triggers Hedgehog-mediated tumor stromal interactions in pancreatic cancer

Spivak-Kroizman, Taly R. ; Hostetter, Galen ; Posner, Richard ; Aziz, Meraj ; Hu, Chengcheng ; Demeure, Michael J. ; Von Hoff, Daniel ; Hingorani, Sunil ; Palculict, Timothy B. ; Izzo, Julie ; Kiriakova, Galina M. ; Abdelmelek, Mena ; Bartholomeusz, Geoffrey ; James, Brian P. ; Powis, Garth

Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of HIF-1α by tumor hypoxia strongly activates secretion of the sonic hedgehog ligand SHH by cancer cells which in turn causes stromal [...]

Menée dans 20 laboratoires du réseau "Physical Sciences-Oncology Centers" sur deux lignées cellulaires de l'épithélium mammaire (une lignée non tumorigène et une lignée métastatique), cette étude met en évidence des différences dans les paramètres cellulaires régulant la morphologie et la survie des cellules

A physical sciences network characterization of non-tumorigenic and metastatic cells

To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture [...]

Cet article passe en revue les perspectives offertes par les connaissances sur les mécanismes biologiques du vieillissement pour la compréhension de la biologie des cancers

How ageing processes influence cancer

de Magalhaes, Joao Pedro

The ageing of populations worldwide is leading to an unprecedented increase in cancer cases and fatalities. Understanding the links between cancer and ageing is therefore more important than ever. How the interplay of ageing-associated changes affects cancer initiation and progression is complex, however, and some ageing processes probably foster cancer development whereas others hinder it, possibly in a tissue-specific manner. In the emerging age of cancer, how can our growing understanding of [...]

Cet article passe en revue les modèles animaux pour l'étude des cancers de la prostate

Animal Models of Human Prostate Cancer: The Consensus Report of the New York Meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee

Ittmann, Michael ; Huang, Jiaoti ; Radaelli, Enrico ; Martin, Philip ; Signoretti, Sabina ; Sullivan, Ruth ; Simons, Brian W. ; Ward, Jerrold M. ; Robinson, Brian D. ; Chu, Gerald C. ; Loda, Massimo ; Thomas, George ; Borowsky, Alexander ; Cardiff, Robert D.

Animal models, particularly mouse models, play a central role in the study of the etiology, prevention, and treatment of human prostate cancer. While tissue culture models are extremely useful in understanding the biology of prostate cancer, they cannot recapitulate the complex cellular interactions within the tumor microenvironment that play a key role in cancer initiation and progression. The National Cancer Institute (NCI) Mouse Models of Human Cancers Consortium convened a group of human [...]

Cet article passe en revue les travaux récents sur la biologie moléculaire et cellulaire des gliomes pédiatriques de bas grade

The molecular and cell biology of pediatric low-grade gliomas

Chen, Y. H. ; Gutmann, D. H.

Pilocytic astrocytoma (PA) is the most common glial cell tumor arising in children. Sporadic cases are associated with KIAA1549:BRAF fusion rearrangements, while 15–20% of children develop PA in the context of the neurofibromatosis 1 (NF1) inherited tumor predisposition syndrome. The unique predilection of these tumors to form within the optic pathway and brainstem (NF1-PA) and cerebellum (sporadic PA) raises the possibility that gliomagenesis requires more than biallelic inactivation of the [...]