Menée à l'aide d'un modèle mathématique, cette étude suggère que, pour les cancers survenant dans des tissus en renouvellement, la majorité des mutations somatiques apparaissent avant le développement de la tumeur

Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation

Tomasetti, Cristian ; Vogelstein, Bert ; Parmigiani, Giovanni

Although it has been hypothesized that some of the somatic mutations found in tumors may occur before tumor initiation, there is little experimental or conceptual data on this topic. To gain insights into this fundamental issue, we formulated a mathematical model for the evolution of somatic mutations in which all relevant phases of a tissue’s history are considered. The model makes the prediction, validated by our empirical findings, that the number of somatic mutations in tumors of [...]

A partir d'échantillons tumoraux prélevés sur 39 patients atteints d'un glioblastome multiforme, 39 patients atteints d'un carcinome du côlon et 60 patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude identifie la présence récurrente de mutations du gène FAT1 en association avec l'activation de la signalisation Wnt et la survie des patients

Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation

Morris, Luc G. T. ; Kaufman, Andrew M. ; Gong, Yongxing ; Ramaswami, Deepa ; Walsh, Logan A. ; Turcan, Sevin ; Eng, Stephanie ; Kannan, Kasthuri ; Zou, Yilong ; Peng, Luke ; Banuchi, Victoria E. ; Paty, Phillip ; Zeng, Zhaoshi ; Vakiani, Efsevia ; Solit, David ; Singh, Bhuvanesh ; Ganly, Ian ; Liau, Linda ; Cloughesy, Timothy C. ; Mischel, Paul S. ; Mellinghoff, Ingo K. ; Chan, Timothy A.

Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila melanogaster tumor suppressor–related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo by binding

Menée in vitro et à l'aide de 203 échantillons prélevés sur des patients atteints d'un lymphome à grandes cellules B, cette étude identifie sur l'ADN des sites fragiles de réplication précoce associés à une instabilité génomique

Identification of Early Replicating Fragile Sites that Contribute to Genome Instability

Barlow, Jacqueline H. ; Faryabi, Robert B ; Callén, Elsa ; Wong, Nancy ; Malhowski, Amy ; Chen, Hua Tang ; Gutierrez-Cruz, Gustavo ; Sun, Hong-Wei ; McKinnon, Peter ; Wright, George ; Casellas, Rafael ; Robbiani, Davide F ; Staudt, Louis ; Fernandez-Capetillo, Oscar ; Nussenzweig, André

DNA double-strand breaks (DSBs) in B lymphocytes arise stochastically during replication or as a result of targeted DNA damage by activation-induced cytidine deaminase (AID). Here we identify recurrent, early replicating, and AID-independent DNA lesions, termed early replication fragile sites (ERFSs), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFSs colocalize with highly expressed gene clusters and are enriched for repetitive elements and CpG [...]

Menée sur 300 échantillons tumoraux prélevés sur des patients atteints d'un méningiome, cette étude identifie des mutations des gènes TRAF7, KLF4, AKT1 et SMO dans les tumeurs ne présentant pas de mutations du gène NF2

Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Clark, Victoria E. ; Erson-Omay, E. Zeynep ; Serin, Akdes ; Yin, Jun ; Cotney, Justin ; Özduman, Koray ; Avşar, Timuçin ; Li, Jie ; Murray, Phillip B. ; Henegariu, Octavian ; Yilmaz, Saliha ; Günel, Jennifer Moliterno ; Carrión-Grant, Geneive ; Yılmaz, Baran ; Grady, Conor ; Tanrıkulu, Bahattin ; Bakırcıoğlu, Mehmet ; Kaymakçalan, Hande ; Caglayan, Ahmet Okay ; Sencar, Leman ; Ceyhun, Emre ; Atik, A. Fatih ; Bayri, Yaşar ; Bai, Hanwen ; Kolb, Luis E. ; Hebert, Ryan ; Omay, S. Bulent ; Mishra-Gorur, Ketu ; Choi, Murim ; Overton, John D. ; Holland, Eric C. ; Mane, Shrikant ; State, Matthew W. ; Bilgüvar, Kaya ; Baehring, Joachim M. ; Gutin, Philip H. ; Piepmeier, Joseph M. ; Vortmeyer, Alexander ; Brennan, Cameron W. ; Pamir, M. Necmettin ; Kılıç, Türker ; Lifton, Richard P. ; Noonan, James P. ; Yasuno, Katsuhito ; Günel, Murat

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of [...]

Cet article passe en revue les travaux récents sur le rôle du gène p63 dans les cancers

p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis

Su, Xiaohua ; Chakravarti, Deepavali ; Flores, Elsa R.

The role of p63 in cancer has been an area of intense debate and controversy. Is TP63 (which encodes p63) a tumour suppressor gene or an oncogene? This debate is partly due to the complexity of the gene. There are several p63 isoforms — some with tumour suppressive functions and others with oncogenic functions. In this Opinion article, we focus on the recent advances in understanding p63 biology and its roles in cancer. In this regard, we discuss the role of p63 in multiple stem cell [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant l'expression de PRKD2, le facteur de transcription GABP favorise le développement d'une leucémie myéloïde chronique

GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2

Yang, Zhong-Fa ; Zhang, Haojian ; Ma, Leyuan ; Peng, Cong ; Chen, Yaoyu ; Wang, Junling ; Green, Michael R. ; Li, Shaoguang ; Rosmarin, Alan G.

Hematopoietic stem cells (HSCs) are the source of all blood lineages, and HSCs must balance quiescence, self-renewal, and differentiation to meet lifelong needs for blood cell development. Transformation of HSCs by the breakpoint cluster region-ABL tyrosine kinase (BCR-ABL) oncogene causes chronic myelogenous leukemia (CML). The E-twenty six (ets) transcription factor GA binding protein (GABP) is a tetrameric transcription factor complex that contains GABPα and GABPβ proteins. Deletion in bone [...]

Menée à l'aide d'une lignée cellulaire d'épithélium canalaire du pancréas et à l'aide de xénogreffes, cette étude met en évidence des mécanismes de la transformation maligne

Deciphering the Mechanisms of Tumorigenesis in Human Pancreatic Ductal Epithelial Cells

Chang, Zhe ; Li, Zhongkui ; Wang, Xiaoyang ; Kang, Ya'an ; Yuan, Yuhui ; Niu, Jiangong ; Wang, Huamin ; Chatterjee, Deyali ; Fleming, Jason B. ; Li, Min ; Abbruzzese, James L. ; Chiao, Paul J.

Purpose: The most common genetic lesions in pancreatic ductal adenocarcinoma (PDAC) have been identified. However, significant gaps still exist in our understanding of how such genetic alterations act in concert to induce PDAC development. In this study, we investigated the mechanism of tumorigenic transformation in the immortalized human pancreatic ductal epithelial (HPDE) cell line by sequentially introducing PDAC signature alterations into this cell line. Experimental Design: The phenotype [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'intégrine bêta 4 favorise le développement d'un cancer de la prostate

β4 Integrin signaling induces expansion of prostate tumor progenitors

Yoshioka, Toshiaki ; Otero, Javier ; Chen, Yu ; Kim, Young-Mi ; Koutcher, Jason A. ; Satagopan, Jaya ; Reuter, Victor ; Carver, Brett ; de Stanchina, Elisa ; Enomoto, Katsuhiko ; Greenberg, Norman M. ; Scardino, Peter T. ; Scher, Howard I. ; Sawyers, Charles L. ; Giancotti, Filippo G.

The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed [...]

Cet article passe en revue les travaux récents sur le rôle du métabolisme du cholestérol dans le développement d'un cancer de la prostate

Cholesterol accumulation in prostate cancer: A classic observation from a modern perspective

Krycer, James Robert ; Brown, Andrew John

Prostate cancer (PCa) is the most common cancer in men in developed countries. Epidemiological studies have associated high blood-cholesterol levels with an increased risk of PCa, whilst cholesterol-lowering drugs (statins) reduce the risk of advanced PCa. Furthermore, normal prostate epithelial cells have an abnormally high cholesterol content, with cholesterol levels increasing further during progression to PCa. In this review, we explore why and how this occurs. Concurrent to this [...]

Menée in vitro et in vivo, cette étude suggère que le gène du récepteur des neurotrophines TrkC joue un rôle de suppresseur de tumeurs dans les cancers colorectaux

Dependence receptor TrkC is a putative colon cancer tumor suppressor

Genevois, Anne-Laure ; Ichim, Gabriel ; Coissieux, Marie-May ; Lambert, Marie-Pierre ; Lavial, Fabrice ; Goldschneider, David ; Jarrosson-Wuilleme, Loraine ; Lepinasse, Florian ; Gouysse, Géraldine ; Herceg, Zdenko ; Scoazec, Jean-Yves ; Tauszig-Delamasure, Servane ; Mehlen, Patrick

The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore [...]

Cet article passe en revue les travaux récents sur le rôle de la voie de signalisation PI3K/Akt dans la régulation de la motilité cellulaire et, en conséquence, dans les processus invasif et métastatique

PKB/Akt–Dependent Regulation of Cell Motility

Xue, Gongda ; Hemmings, Brian A.

The prosurvival activity of phosphoinositide 3 kinase (PI3K)/Akt (also known as protein kinase B, PKB) pathway has been investigated in great detail in human physiology and disease. Accumulating evidence is emerging that this signaling axis also actively engages with the migratory process in motile cells, including metastatic cancer cells. Interference with the role of PI3K/Akt–mediated cell motility impairs cellular development and attenuates malignant progression of cancer metastasis. Because [...]

Menée sur des échantillons de multiples métastases prélevés lors d'une autopsie de 13 patients décédés d'un cancer de la prostate, cette étude met en évidence, pour chaque patient, une homogénéité des anomalies de méthylation de l'ADN dans les métastases et, entre patients, une hétérogénéité de ces anomalies

DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases

Aryee, Martin J. ; Liu, Wennuan ; Engelmann, Julia C. ; Nuhn, Philipp ; Gurel, Meltem ; Haffner, Michael C. ; Esopi, David ; Irizarry, Rafael A. ; Getzenberg, Robert H. ; Nelson, William G. ; Luo, Jun ; Xu, Jianfeng ; Isaacs, William B. ; Bova, G. Steven ; Yegnasubramanian, Srinivasan

Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation [...]

Menée in vitro, in vivo et à l'aide d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du micro-ARN 29b dans le micro-environnement tumoral, le facteur de transcription GATA3 inhibe le processus métastatique

GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression

Chou, Jonathan ; Lin, Jeffrey H. ; Brenot, Audrey ; Kim, Jung-whan ; Provot, Sylvain ; Werb, Zena

Despite advances in our understanding of breast cancer, patients with metastatic disease have poor prognoses. GATA3 is a transcription factor that specifies and maintains mammary luminal epithelial cell fate, and its expression is lost in breast cancer, correlating with a worse prognosis in human patients. Here, we show that GATA3 promotes differentiation, suppresses metastasis and alters the tumour microenvironment in breast cancer by inducing microRNA-29b (miR-29b) expression. Accordingly, [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par une enzyme, Rab25, dans le processus métastatique d'un carcinome épidermoïde de la tête et du cou

Rab25 regulates invasion and metastasis in head and neck cancer

Amornphimoltham, Panomwat ; Rechache, Kamil ; Thompson, Jamie ; Masedunskas, Andrius ; Leelahavanichkul, Kantima ; Patel, Vyomesh ; Molinolo, Alfredo ; Gutkind, J. Silvio ; Weigert, Roberto

Purpose:Head and neck squamous cell carcinoma (HNSCC) is one of the ten most common cancers with a 50% five-year survival rate, which has remained unchanged for the past three decades. One of the major reasons for the aggressiveness of this cancer is that HNSCCs readily metastasize to cervical lymph nodes that are abundant in the head and neck region. Hence, discovering new molecules controlling the metastatic process as well as understanding their regulation at the molecular level are [...]

Cet article évalue l'intérêt, pour identifier l'origine cellulaire de différentes tumeurs solides, de modèles murins permettant de moduler l'expression d'oncogènes et/ou de suppresseurs de tumeurs

Tracing the cellular origin of cancer

Blanpain, Cedric

Although many genes that lead to different types of cancer when mutated have been identified, the cells that initiate tumour formation following accumulation of these mutations have, until recently, remained elusive. This review explores how mouse genetic lineage-tracing experiments that allow the expression of oncogenes and/or the deletion of tumour suppressor genes in defined cell lineages have been instrumental in defining the cellular origin of different solid tumours in mouse models for [...]