A partir d'échantillons tumoraux prélevés sur plusieurs cohortes de patients atteints d'un gliome, cette étude identifie de fréquentes mutations somatiques du gène PPM1D dans les gliomes du tronc cérébral

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Zhang, Liwei ; Chen, Lee H. ; Wan, Hong ; Yang, Rui ; Wang, Zhaohui ; Feng, Jie ; Yang, Shaohua ; Jones, Sian ; Wang, Sizhen ; Zhou, Weixin ; Zhu, Huishan ; Killela, Patrick J. ; Zhang, Junting ; Wu, Zhen ; Li, Guilin ; Hao, Shuyu ; Wang, Yu ; Webb, Joseph B. ; Friedman, Henry S. ; Friedman, Allan H. ; McLendon, Roger E. ; He, Yiping ; Reitman, Zachary J. ; Bigner, Darell D. ; Yan, Hai

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53–induced [...]

A partir d'échantillons tumoraux prélevés sur 62 patients atteints d'une tumeur germinale intracrânienne, cette étude identifie de nouvelles mutations somatiques et constitutionnelles associées à la maladie

Novel somatic and germline mutations in intracranial germ cell tumours

Wang, Linghua ; Yamaguchi, Shigeru ; Burstein, Matthew D. ; Terashima, Keita ; Chang, Kyle ; Ng, Ho-Keung ; Nakamura, Hideo ; He, Zongxiao ; Doddapaneni, Harshavardhan ; Lewis, Lora ; Wang, Mark ; Suzuki, Tomonari ; Nishikawa, Ryo ; Natsume, Atsushi ; Terasaka, Shunsuke ; Dauser, Robert ; Whitehead, William ; Adekunle, Adesina ; Sun, Jiayi ; Qiao, Yi ; Marth, Gabor ; Muzny, Donna M. ; Gibbs, Richard A. ; Leal, Suzanne M. ; Wheeler, David A. ; Lau, Ching C.

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are [...]

A partir d'échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, puis menée in vitro et in vivo, cette étude met en évidence l'existence, au sein d'une même tumeur, d'une hétérogénéité des mutations du gène EGFR

EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing

Francis, Joshua M ; Zhang, Cheng-Zhong ; Maire, Cecile L ; Jung, Joonil ; Manzo, Veronica E ; Adalsteinsson, Viktor A ; Homer, Heather ; Haidar, Sam ; Blumenstiel, Brendan ; Pedamallu, Chandra Sekhar ; Ligon, Azra H ; Love, J. Christopher ; Meyerson, Matthew ; Ligon, Keith L

Glioblastomas with EGFR amplification represent approximately 50% of newly diagnosed cases and recent studies have revealed frequent coexistence of multiple EGFR aberrations within the same tumor with implications for mutation cooperation and treatment resistance. However, bulk tumor sequencing studies cannot resolve the patterns of how the multiple EGFR aberrations coexist with other mutations within single tumor cells. Here we applied a population-based single-cell whole genome sequencing [...]

Cette étude italienne passe en revue les travaux récents sur le rôle de la mutation V600E du gène BRAF dans le développement d'un carcinome papillaire de la thyroïde

Time to re-consider the meaning of BRAF V600E mutation in papillary thyroid carcinoma

Gandolfi, Greta ; Sancisi, Valentina ; Piana, Simonetta ; Ciarrocchi, Alessia

The BRAF V600E mutation, resulting from the BRAFT1799A transversion, is the most common genetic mutation in papillary thyroid carcinoma (PTC), with a mean frequency close to 50% among all cases. A large number of studies in the past decade have tried to dissect the relevance and the function of the V600E mutation in controlling oncogenesis and progression of thyroid cancer. However, several works published in the latest years have provided new evidence, in partial conflict with the previous [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels la protéine BRCA2 régule une instabilité génomique associée au cancer

BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2

Bhatia, Vaibhav ; Barroso, Sonia I. ; Garcia-Rubio, Maria L. ; Tumini, Emanuela ; Herrera-Moyano, Emilia ; Aguilera, Andres

Genome instability is central to ageing, cancer and other diseases. It is not only proteins involved in DNA replication or the DNA damage response (DDR) that are important for maintaining genome integrity: from yeast to higher eukaryotes, mutations in genes involved in pre-mRNA splicing and in the biogenesis and export of messenger ribonucleoprotein (mRNP) also induce DNA damage and genome instability. This instability is frequently mediated by R-loops formed by DNA–RNA hybrids and a displaced [...]

A partir d'échantillons de tumeurs primitives et de métastases pulmonaires prélevés sur 53 patientes atteintes d'un cancer du sein, cette étude identifie des mutations dans deux gènes, RPL39 et MLF2, influençant la capacité d'auto-renouvellement des cellules souches cancéreuses

Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling

Dave, Bhuvanesh ; Granados-Principal, Sergio ; Zhu, Rui ; Benz, Stephen ; Rabizadeh, Shahrooz ; Soon-Shiong, Patrick ; Yu, Ke-Da ; Shao, Zhimin ; Li, Xiaoxian ; Gilcrease, Michael ; Lai, Zhao ; Chen, Yidong ; Huang, Tim H.-M. ; Shen, Haifa ; Liu, Xuewu ; Ferrari, Mauro ; Zhan, Ming ; Wong, Stephen T. C. ; Kumaraswami, Muthiah ; Mittal, Vivek ; Chen, Xi ; Gross, Steven S. ; Chang, Jenny C.

We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knockdown of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels des cellules de cancer du côlon sont susceptibles, après avoir formé des lésions hépatiques, de créer des métastases pulmonaires

Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH

Urosevic, Jelena ; Garcia-Albeniz, Xabier ; Planet, Evarist ; Real, Sebastián ; Céspedes, María Virtudes ; Guiu, Marc ; Fernández, Esther ; Bellmunt, Anna ; Gawrzak, Sylwia ; Pavlovic, Milica ; Mangues, Ramón ; Dolado, Ignacio ; Barriga, Francisco M. ; Nadal, Cristina ; Kemeny, Nancy ; Batlle, Eduard ; Nebreda, Angel R. ; Gomis, Roger R.

The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS mutation influences where and when metastasis occurs, are unknown. We provide clinical and molecular evidence showing that different MAPK signalling pathways are implicated in this process. Whereas ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver, reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously [...]