A partir de données génomiques portant sur plus de 8 000 échantillons tumoraux, cette étude identifie, pour environ 3,5% des cas, la présence d'insertions et délétions complexes dans plusieurs gènes associés au cancer

Systematic discovery of complex insertions and deletions in human cancers

Ye, Kai ; Wang, Jiayin ; Jayasinghe, Reyka ; Lameijer, Eric-Wubbo ; McMichael, Joshua F. ; Ning, Jie ; McLellan, Michael D. ; Xie, Mingchao ; Cao, Song ; Yellapantula, Venkata ; Huang, Kuan-lin ; Scott, Adam ; Foltz, Steven ; Niu, Beifang ; Johnson, Kimberly J. ; Moed, Matthijs ; Slagboom, P. Eline ; Chen, Feng ; Wendl, Michael C. ; Ding, Li

Complex insertions and deletions (indels) are formed by simultaneously deleting and inserting DNA fragments of different sizes at a common genomic location. Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were [...]

A partir de 24 échantillons prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude identifie un ensemble de réarrangements génomiques de grande ampleur impliqués dans le développement de la maladie

Integrated genomic analysis of pancreatic ductal adenocarcinomas reveals genomic rearrangement events as significant drivers of disease

Murphy, Stephen J ; Hart, Steven N. ; Halling, Geoffrey ; Johnson, Sarah H ; Smadbeck, James B ; Drucker, Travis ; Felipe Lima, Joema ; Rakhshan Rohakhtar, Fariborz ; Harris, Faye R ; Kosari, Farhad ; Subramanian, Subbaya ; Petersen, Gloria M. ; Wiltshire, Timothy D ; Kipp, Benjamin R ; Truty, Mark J ; McWilliams, Robert R. ; Couch, Fergus J. ; Vasmatzis, George

Many somatic mutations have been detected in pancreatic ductal adenocarcinoma (PDAC) leading to the identification of some key drivers of disease progression, but the involvement of large genomic rearrangements has often been overlooked. In this study, we performed mate pair sequencing (MPseq) on genomic DNA from 24 PDAC tumors, including 15 laser-captured microdissected PDAC and 9 patient-derived xenografts, to identify genome-wide rearrangements. Large genomic rearrangements with intragenic [...]

A partir d'échantillons tumoraux prélevés sur 20 patients atteints d'un carcinome épidermoïde avancé du pénis (âge médian : 60 ans), cette étude identifie un ensemble d'anomalies génomiques susceptibles d'induire la prescription d'une thérapie ciblée

Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations

Ali, Siraj M. ; Pal, Sumanta K. ; Wang, Kai ; Palma, Norma A. ; Sanford, Eric ; Bailey, Mark ; He, Jie ; Elvin, Julia A. ; Chmielecki, Juliann ; Squillace, Rachel ; Dow, Edward ; Morosini, Deborah ; Buell, Jamie ; Yelensky, Roman ; Lipson, Doron ; Frampton, Garrett M. ; Howley, Peter ; Ross, Jeffrey S. ; Stephens, Philip J. ; Miller, Vincent A.

Background : Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. Comprehensive genomic profiling (CGP) was performed to identify clinically relevant genomic alterations (CRGAs). Materials and Methods : DNA was extracted from 40  [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels le micro-ARN miR-31 favorise le développement d'un adénocarcinome du poumon

MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer

Edmonds, Mick D. ; Boyd, Kelli L. ; Moyo, Tamara ; Mitra, Ramkrishna ; Duszynski, Robert ; Arrate, Maria Pia ; Chen, Xi ; Zhao, Zhongming ; Blackwell, Timothy S. ; Andl, Thomas ; Eischen, Christine M.

MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en interagissant avec des cellules endothéliales, des cellules tumorales circulant dans les vaisseaux sanguins favorisent le processus métastatique

Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype

Connor, Yamicia ; Tekleab, Sarah ; Nandakumar, Shyama ; Walls, Cherelle ; Tekleab, Yonatan ; Husain, Amjad ; Gadish, Or ; Sabbisetti, Venkata ; Kaushik, Shelly ; Sehrawat, Seema ; Kulkarni, Ashish ; Dvorak, Harold ; Zetter, Bruce ; R. Edelman, Elazer ; Sengupta, Shiladitya

Metastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates [...]

Menée in vitro et in vivo sur des modèles de cancer du sein triplement négatif, cette étude met en évidence des mécanismes par lesquels la perte d'expression de la protéine SSBP1 favorise le processus métastatique

SSBP1 Suppresses TGF-β-Driven Epithelial-to-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer by Regulating Mitochondrial Retrograde Signaling

Jiang, Honglin ; Sun, He-fen ; Gao, Shui-ping ; Li, Liang-dong ; Huang, Sheng ; Hu, Xin ; Liu, Sheng ; Wu, Jiong ; Shao, Zhi-Ming ; Jin, Wei

Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype lacking effective prognostic indicators or therapeutic targets. Mitochondrial function is dysregulated frequently in cancer cells to allow for adaptation to a harsh tumor microenvironment. Targeting mitochondrial biogenesis and bioenergetics is therefore an attractive therapeutic strategy. In this study, we performed quantitative proteomic analyses in human parental and metastatic breast cancer cell lines to identify [...]

Cet article passe en revue les travaux récents sur la réponse cellulaire à divers agents portant atteinte à l'intégrité de l'ADN

DNA damage and the balance between survival and death in cancer biology

Roos, Wynand P. ; Thomas, Adam D. ; Kaina, Bernd

DNA is vulnerable to damage resulting from endogenous metabolites, environmental and dietary carcinogens, some anti-inflammatory drugs, and genotoxic cancer therapeutics. Cells respond to DNA damage by activating complex signalling networks that decide cell fate, promoting not only DNA repair and survival but also cell death. The decision between cell survival and death following DNA damage rests on factors that are involved in DNA damage recognition, and DNA repair and damage tolerance, as [...]

Cet article passe en revue l'histoire des travaux scientifiques sur le rôle des mécanismes de réparation de l'ADN dans la biologie des cancers

DNA repair, genome stability and cancer: a historical perspective

Jeggo, Penny A. ; Pearl, Laurence H. ; Carr, Antony M.

The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy.