A partir de 75 échantillons tumoraux prélevés sur des patients atteints d'un neuroblastome de stade avancé, cette étude de séquençage du génome entier identifie la présence fréquente de réarrangements structuraux induisant une surexpression du gène TERT, puis montre que la présence de ces réarrangements est associée à un pronostic défavorable

TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors

Valentijn, Linda J. ; Koster, Jan ; Zwijnenburg, Danny A. ; Hasselt, Nancy E. ; van Sluis, Peter ; Volckmann, Richard ; van Noesel, Max M. ; George, Rani E. ; Tytgat, Godelieve A. M. ; Molenaar, Jan J. ; Versteeg, Rogier

Whole-genome sequencing detected structural rearrangements of TERT in 17 of 75 high-stage neuroblastomas, with five cases resulting from chromothripsis. Rearrangements were associated with increased TERT expression and targeted regions immediately up- and downstream of TERT, positioning a super-enhancer close to the breakpoints in seven cases. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non-overlapping groups of high-stage neuroblastoma, [...]

A partir de 161 échantillons tumoraux prélevés sur des patients atteints d'un carcinome papillaire rénal primitif, cette étude identifie des anomalies moléculaires spécifiquement associées au type 1 et au type 2 de la maladie

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

BACKGROUND : Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS : We performed comprehensive molecular [...]

Menée sur des lignées cellulaires, cette étude met en évidence le rôle joué par des mutations de la région amino-terminale du gène suppresseur de tumeurs p53 dans la survie des cellules cancéreuses

Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis

Phang, Beng Hooi ; Othman, Rashidah ; Bougeard, Gaelle ; Chia, Ren Hui ; Frebourg, Thierry ; Tang, Choong Leong ; Cheah, Peh Yean ; Sabapathy, Kanaga

Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to [...]

Menée à l'aide de modèles murins de cancer de la peau, cette étude suggère que la plupart des métastases sont dues à une dissémination synchrone à partir de la tumeur primitive

Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers

McCreery, Melissa Q. ; Halliwill, Kyle D. ; Chin, Douglas ; Delrosario, Reyno ; Hirst, Gillian ; Vuong, Peter ; Jen, Kuang-Yu ; Hewinson, James ; Adams, David J. ; Balmain, Allan

Human tumors show a high level of genetic heterogeneity, but the processes that influence the timing and route of metastatic dissemination of the subclones are unknown. Here we have used whole-exome sequencing of 103 matched benign, malignant and metastatic skin tumors from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumor, supporting parallel rather than linear evolution as the predominant model of metastasis. Shared mutations [...]

Menée à l'aide de modélisations inspirées de la physique statistique, cette étude analyse le rôle de l'expression d'ARNs non codants dans les cellules cancéreuses et leurs relations avec le micro-environnement tumoral

Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Tanne, Antoine ; Muniz, Luciana R. ; Puzio-Kuter, Anna ; Leonova, Katerina I. ; Gudkov, Andrei V. ; Ting, David T. ; Monasson, Rémi ; Cocco, Simona ; Levine, Arnold J. ; Bhardwaj, Nina ; Greenbaum, Benjamin D.

Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is [...]

Cette étude évalue l'intérêt d'organoïdes, réalisés à partir de cellules tumorales d'un patient atteint d'un adénocarcinome du pancréas, pour tester la réponse à divers traitements

Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids

Huang, Ling ; Holtzinger, Audrey ; Jagan, Ishaan ; BeGora, Michael ; Lohse, Ines ; Ngai, Nicholas ; Nostro, Cristina ; Wang, Rennian ; Muthuswamy, Lakshmi B. ; Crawford, Howard C. ; Arrowsmith, Cheryl ; Kalloger, Steve E. ; Renouf, Daniel J. ; Connor, Ashton A. ; Cleary, Sean ; Schaeffer, David F. ; Roehrl, Michael ; Tsao, Ming-Sound ; Gallinger, steven ; Keller, Gordon ; Muthuswamy, Senthil K.

There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induces cytosolic SOX9 [...]