Menée sur des échantillons tumoraux prélevés sur 32 patients atteints d'un adénocarcinome mucineux invasif du poumon (5 avec mutations du gène KRAS, 27 sans), cette étude identifie des fusions de gènes impliquées dans le développement de tumeurs en l'absence de mutations du gène KRAS, puis montre que des cellules exprimant ces fusions sont sensibles à des inhibiteurs de tyrosine kinase

Druggable Oncogene Fusions in Invasive Mucinous Lung Adenocarcinoma

Nakaoku, Takashi ; Tsuta, Koji ; Ichikawa, Hitoshi ; Shiraishi, Kouya ; Sakamoto, Hiromi ; Enari, Masato ; Furuta, Koh ; Shimada, Yoko ; Ogiwara, Hideaki ; Watanabe, Shun-ichi ; Nokihara, Hiroshi ; Yasuda, Kazuki ; Hiramoto, Masaki ; Nammo, Takao ; Ishigame, Teruhide ; Schetter, Aaron J ; Okayama, Hirokazu ; Harris, Curtis C. ; Kim, Young Hak ; Mishima, Michiaki ; Yokota, Jun ; Yoshida, Teruhiko ; Kohno, Takashi

Purpose: To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma (IMA) of the lung, a malignant type of lung adenocarcinoma in which KRAS mutations frequently occur. Experimental Design: From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations and 34 cases without (38%), we conducted whole-transcriptome sequencing of 32 IMAs, including 27 cases without KRAS mutations. We used the sequencing data to identify gene fusions, and then performed functional [...]

A partir de données portant sur 923 patientes atteintes d'un cancer du sein et sur 1 769 patients atteints d'autres types de cancer (11 différents), cette étude montre que, pour les femmes porteuses d'une anomalie génomique constitutionnelle supprimant l'expression de la cytidine désaminase APOBEC3B, les tumeurs présentent un nombre plus élevé de mutations que les tumeurs des femmes non porteuses de cette mutation

Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer

Nik-Zainal, Serena ; Wedge, David C. ; Alexandrov, Ludmil B. ; Petljak, Mia ; Butler, Adam P. ; Bolli, Niccolo ; Davies, Helen R. ; Knappskog, Stian ; Martin, Sancha ; Papaemmanuil, Elli ; Ramakrishna, Manasa ; Shlien, Adam ; Simonic, Ingrid ; Xue, Yali ; Tyler-Smith, Chris ; Campbell, Peter J. ; Stratton, Michael R.

The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures and a signature of localized hypermutation called [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par la protéine Lin28 dans le développement du rein et la formation d'une tumeur de Wilms

Lin28 sustains early renal progenitors and induces Wilms tumor

Urbach, Achia ; Yermalovich, Alena ; Zhang, Jin ; Spina, Catherine S. ; Zhu, Hao ; Perez-Atayde, Antonio R. ; Shukrun, Rachel ; Charlton, Jocelyn ; Sebire, Neil ; Mifsud, William ; Dekel, Benjamin ; Pritchard-Jones, Kathy ; Daley, George Q.

Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only [...]

Menée in vitro, cette étude met en évidence le rôle joué par une amplification des centrosomes dans la transformation maligne

Oncogene-like induction of cellular invasion from centrosome amplification

Godinho, Susana A. ; Picone, Remigio ; Burute, Mithila ; Dagher, Regina ; Su, Ying ; Leung, Cheuk T. ; Polyak, Kornelia ; Brugge, Joan S. ; Thery, Manuel ; Pellman, David

Centrosome amplification has long been recognized as a feature of human tumours; however, its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumours, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote [...]

Cet article passe en revue les travaux récents sur les mécanismes épigénétiques de régulation de la transition épithélio-mésenchymateuse dans les cellules de cancer du sein

Role of epigenetic mechanisms in epithelial-to-mesenchymal transition of breast cancer cells

Nickel, Annina ; Stadler, Sonja C.

The epithelial-mesenchymal-transition (EMT) is a crucial process during normal development that allows dynamic and reversible shifts between epithelial and mesenchymal cell states. Cancer cells take advantage of the complex, interrelated cellular networks that regulate EMT, to promote their migratory and invasive capabilities. Over the last years, evidence accumulated that not only genetic mutations but also changes to epigenetic mechanisms are key drivers of EMT in cancer cells. Recent studies [...]

Menée in vitro, in vivo et à partir de données d'expression de gènes portant sur des patientes atteintes d'un cancer du sein ER-, cette étude met en évidence des mécanismes par lesquels l'enzyme NOS2 favorise la résistance thérapeutique et le processus métastatique

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Heinecke, Julie L. ; Ridnour, Lisa A. ; Cheng, Robert Y. S. ; Switzer, Christopher H. ; Lizardo, Michael M. ; Khanna, Chand ; Glynn, Sharon A. ; Hussain, S. Perwez ; Young, Howard A. ; Ambs, Stefan ; Wink, David A.

Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression [...]

Cet article passe en revue les travaux récents sur le rôle des cellules souches cancéreuses dans le processus métastatique d'un cancer du sein

Breast Cancer Stem Cells: Multiple Capacities in Tumor Metastasis

Geng, Shao-Qing ; Alexandrou, Aris T. ; Li, Jian Jian

Breast cancer is the leading cause of cancer death among women worldwide. Accumulating evidence indicates that the local recurrent and/or distant metastatic tumors, the major causes of lethality in the clinic, are related to the aggressive phenotype of a small fraction of cancer cells loosely termed as cancer stem cells (CSCs), tumor initiating cells (TICs), or cancer metastasis-initiating cells (CMICs). Breast cancer stem cells (BCSCs) are shown to exhibit unique growth abilities including [...]