A partir de données génomiques portant sur 652 tumeurs, cette étude montre que des différences dans la réparation des mésappariements de l'ADN sont à l'origine des variations du taux de mutations sur le génome humain

Differential DNA mismatch repair underlies mutation rate variation across the human genome

Supek, Fran ; Lehner, Ben

Cancer genome sequencing has revealed considerable variation in somatic mutation rates across the human genome, with mutation rates elevated in heterochromatic late replicating regions and reduced in early replicating euchromatin. Multiple mechanisms have been suggested to underlie this, but the actual cause is unknown. Here we identify variable DNA mismatch repair (MMR) as the basis of this variation. Analysing ~17 million single-nucleotide variants from the genomes of 652 tumours, we show [...]

A partir de données génomiques issues de 173 échantillons tumoraux prélevés sur des patients atteints d'un cancer (8 types différents), cette étude montre notamment que le type cellulaire à l'origine de la tumeur peut être déterminé à partir de la distribution des mutations sur le génome

Cell-of-origin chromatin organization shapes the mutational landscape of cancer

Polak, Paz ; Karlic, Rosa ; Koren, Amnon ; Thurman, Robert ; Sandstrom, Richard ; Lawrence, Michael S. ; Reynolds, Alex ; Rynes, Eric ; Vlahovicek, Kristian ; Stamatoyannopoulos, John A. ; Sunyaev, Shamil R.

Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold in the local density of cancer somatic mutations, posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape. However, both somatic mutagenesis and epigenomic features are highly [...]

A partir de 265 paires d'échantillons de tumeurs primitives et de métastases prélevés sur des patients atteints d'une tumeur solide, cette étude identifie notamment des mutations des gènes PIK3CA, SMAD4 et TP53 présentes spécifiquement dans les métastases

Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors

Goswami, Rashmi S ; Patel, Keyur P ; Singh, Rajesh R ; Meric-Bernstam, Funda ; Kopetz, Scott ; Subbiah, Vivek ; Alvarez, Ricardo H ; Davies, Michael A. ; Jabbar, Kausar J. ; Roy Chowdhuri, Sinchita ; Lazar, Alexander J. ; Medeiros, L. Jeffrey ; Broaddus, Russell R. ; Luthra, Rajyalakshmi ; Routbort, Mark J

Purpose: We used a clinical next-generation sequencing hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors. Experimental Design: A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type, percentage tumor, mutational variant frequency, time interval between [...]

A partir de 59 échantillons tumoraux prélevés de façon séquentielle sur 22 patients atteints d'un lymphome folliculaire, cette étude suggère qu'une mutation du gène CREBBP est un événement précoce dans l'évolution de la maladie contribuant à l'échappement au système immunitaire

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green, Michael R. ; Kihira, Shingo ; Liu, Chih Long ; Nair, Ramesh V. ; Salari, Raheleh ; Gentles, Andrew J. ; Irish, Jonathan ; Stehr, Henning ; Vicente-Dueñas, Carolina ; Romero-Camarero, Isabel ; Sanchez-Garcia, Isidro ; Plevritis, Sylvia K. ; Arber, Daniel A. ; Batzoglou, Serafim ; Levy, Ronald ; Alizadeh, Ash A.

Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of [...]

A partir d'échantillons tumoraux prélevés sur 100 patients atteints d'un adénocarcinome canalaire du pancréas, cette étude identifie un ensemble d'anomalies génomiques associées au développement de la maladie ou à la réponse thérapeutique

Whole genomes redefine the mutational landscape of pancreatic cancer

Waddell, Nicola ; Pajic, Marina ; Patch, Ann-Marie ; Chang, David K. ; Kassahn, Karin S. ; Bailey, Peter ; Johns, Amber L. ; Miller, David ; Nones, Katia ; Quek, Kelly ; Quinn, Michael C. J. ; Robertson, Alan J. ; Fadlullah, Muhammad Z. H. ; Bruxner, Tim J. C. ; Christ, Angelika N. ; Harliwong, Ivon ; Idrisoglu, Senel ; Manning, Suzanne ; Nourse, Craig ; Nourbakhsh, Ehsan ; Wani, Shivangi ; Wilson, Peter J. ; Markham, Emma ; Cloonan, Nicole ; Anderson, Matthew J. ; Fink, J. Lynn ; Holmes, Oliver ; Kazakoff, Stephen H. ; Leonard, Conrad ; Newell, Felicity ; Poudel, Barsha ; Song, Sarah ; Taylor, Darrin ; Waddell, Nick ; Wood, Scott ; Xu, Qinying ; Wu, Jianmin ; Pinese, Mark ; Cowley, Mark J. ; Lee, Hong C. ; Jones, Marc D. ; Nagrial, Adnan M. ; Humphris, Jeremy ; Chantrill, Lorraine A. ; Chin, Venessa ; Steinmann, Angela M. ; Mawson, Amanda ; Humphrey, Emily S. ; Colvin, Emily K. ; Chou, Angela ; Scarlett, Christopher J. ; Pinho, Andreia V. ; Giry-Laterriere, Marc ; Rooman, Ilse ; Samra, Jaswinder S. ; Kench, James G. ; Pettitt, Jessica A. ; Merrett, Neil D. ; Toon, Christopher ; Epari, Krishna ; Nguyen, Nam Q. ; Barbour, Andrew ; Zeps, Nikolajs ; Jamieson, Nigel B. ; Graham, Janet S. ; Niclou, Simone P. ; Bjerkvig, Rolf ; Grutzmann, Robert ; Aust, Daniela ; Hruban, Ralph H. ; Maitra, Anirban ; Iacobuzio-Donahue, Christine A. ; Wolfgang, Christopher L. ; Morgan, Richard A. ; Lawlor, Rita T. ; Corbo, Vincenzo ; Bassi, Claudio ; Falconi, Massimo ; Zamboni, Giuseppe ; Tortora, Giampaolo ; Tempero, Margaret A. ; Australian Pancreatic Cancer Genome, Initiative ; Gill, Anthony J. ; Eshleman, James R. ; Pilarsky, Christian ; Scarpa, Aldo ; Musgrove, Elizabeth A. ; Pearson, John V. ; Biankin, Andrew V. ; Grimmond, Sean M.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation [...]

Cet article passe en revue les travaux récents sur la fonction de suppresseur de tumeurs attribuée à la méthyltransférase DNMT3A

DNMT3A in haematological malignancies

Yang, Liubin ; Rau, Rachel ; Goodell, Margaret A.

DNA methylation patterns are disrupted in various malignancies, suggesting a role in the development of cancer, but genetic aberrations directly linking the DNA methylation machinery to malignancies were rarely observed, so this association remained largely correlative. Recently, however, mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) were reported in patients with acute myeloid leukaemia (AML), and subsequently in patients with various other haematological malignancies, [...]

Menée in vitro et in vivo à l'aide du système CRISPR-Cas9 permettant l'édition ciblée du génome, cette étude identifie un ensemble de gènes dont les mutations sont associées au comportement invasif de cellules tumorales de l'intestin

Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids

Matano, Mami ; Date, Shoichi ; Shimokawa, Mariko ; Takano, Ai ; Fujii, Masayuki ; Ohta, Yuki ; Watanabe, Toshiaki ; Kanai, Takanori ; Sato, Toshiro

Human colorectal tumors bear recurrent mutations in genes encoding proteins operative in the WNT, MAPK, TGF-

Cet article passe en revue les travaux récents sur les mécanismes de régulation du processus métastatique impliquant une interaction entre apoptose, autophagie et nécroptose

Apoptosis, autophagy, necroptosis, and cancer metastasis

Su, Zhenyi ; Yang, Zuozhang ; Xu, Yongqing ; Chen, Yongbin ; Yu, Qiang

Metastasis is a crucial hallmark of cancer progression, which involves numerous factors including the degradation of the extracellular matrix (ECM), the epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, the development of an inflammatory tumor microenvironment, and defects in programmed cell death. Programmed cell death, such as apoptosis, autophagy, and necroptosis, plays crucial roles in metastatic processes. Malignant tumor cells must overcome these various forms of cell death [...]

Menée sur des lignées cellulaires, à l'aide de xénogreffes et à partir de données portant sur 311 patients atteints d'un mélanome, cette étude met en évidence des mécanismes par lesquels le facteur de transcription BPTF favorise la progression tumorale et la résistance aux inhibiteurs de BRAF

The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy

Dar, Altaf A. ; Nosrati, Mehdi ; Bezrookove, Vladimir ; De Semir, David ; Majid, Shahana ; Thummala, Suresh ; Sun, Vera ; Tong, Schuyler ; Leong, Stanley P. L. ; Minor, David ; Billings, Paul R. ; Soroceanu, Liliana ; Debs, Robert ; Miller, James R. ; Sagebiel, Richard W. ; Kashani-Sabet, Mohammed

Background: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma. Methods: The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF [...]

A partir d'échantillons de tumeurs primitives et de métastases prélevés sur 53 patients atteints d'un adénocarcinome canalaire du pancréas, cette étude suggère que les tumeurs primitives et les métastases sont dotées d'un stroma fibreux similaire

Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer

Whatcott, Clifford J ; Diep, Caroline H ; Jiang, Ping ; Watanabe, Aprill ; LoBello, Janine ; Sima, Chao ; Hostetter, Galen ; Shepard, H. Michael ; Von Hoff, Daniel D. ; Han, Haiyong

Purpose : Pancreatic ductal adenocarcinoma (PDAC) is characterized by high levels of fibrosis, termed desmoplasia, which is thought to hamper the efficacy of therapeutics treating PDAC. Our primary focus was to evaluate differences in the extent of desmoplasia in primary tumors and metastatic lesions. As metastatic burden is a primary cause for mortality in PDAC, the extent of desmoplasia in metastases may help to determine whether desmoplasia targeting therapeutics will benefit patients with [...]

Menée à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels l'expression, dans des cellules du stroma, de plusieurs gènes spécifiques favorise la progression d'un sous-type de cancer colorectal de pronostic défavorable

Stromal contribution to the colorectal cancer transcriptome

Isella, Claudio ; Terrasi, Andrea ; Bellomo, Sara Erika ; Petti, Consalvo ; Galatola, Giovanni ; Muratore, Andrea ; Mellano, Alfredo ; Senetta, Rebecca ; Cassenti, Adele ; Sonetto, Cristina ; Inghirami, Giorgio ; Trusolino, Livio ; Fekete, Zsolt ; De Ridder, Mark ; Cassoni, Paola ; Storme, Guy ; Bertotti, Andrea ; Medico, Enzo

Recent studies identified a poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC). We noted that genes upregulated in this subtype are also prominently expressed by stromal cells, suggesting that SSM transcripts could derive from stromal rather than epithelial cancer cells. To test this hypothesis, we analyzed CRC expression data from patient-derived xenografts, where mouse stroma supports human cancer cells. Species-specific expression analysis [...]

Cet article passe en revue les travaux récents sur les mécanismes de formation de métastases hépatiques d'un cancer du sein

Mechanisms involved in breast cancer liver metastasis

Ma, Rui ; Feng, Yili ; Lin, Shuang ; Chen, Jiang ; Lin, Hui ; Liang, Xiao ; Zheng, Heming ; Cai, Xiujun

Liver metastasis is a frequent occurrence in patients with breast cancer; however, the available treatments are limited and ineffective. While liver-specific homing of breast cancer cells is an important feature of metastasis, the formation of liver metastases is not random. Indeed, breast cancer cell factors contribute to the liver microenvironment. Major breakthroughs have been achieved recently in understanding breast cancer liver metastasis (BCLM). The process of liver metastasis consists [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels les cassures de l'ADN associées à l'activité des topoisomérases favorisent le développement de divers types de cancer

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

Ashour, Mohamed E. ; Atteya, Reham ; El-Khamisy, Sherif F.

The mammalian genome is constantly challenged by exogenous and endogenous threats. Although much is known about the mechanisms that maintain DNA and RNA integrity, we know surprisingly little about the mechanisms that underpin the pathology and tissue specificity of many disorders caused by defective responses to DNA or RNA damage. Of the different types of endogenous damage, protein-linked DNA breaks (PDBs) are emerging as an important player in cancer development and therapy. PDBs can arise [...]

Menée à l'aide de modèles murins, cette étude évalue l'intérêt d'un modèle qui, à base d'un ensemble de biomarqueurs, prédit l'évolution hétérogène de tumeurs du sein ERBB2+

Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach

Castellanos-Martin, Andres ; Castillo-Lluva, Sonia ; Saez-Freire, Maria ; Blanco-Gomez, Adrian ; Hontecillas-Prieto, Lourdes ; Patino-Alonso, Carmen ; Galindo-Villardon, Purificacion ; del Villar, Luis ; Martin-Seisdedos, Carmen ; Isidoro-Garcia, Maria ; Abad-Hernandez, Maria ; Cruz-Hernandez, Juan ; Rodriguez-Sanchez, Cesar ; Gonzalez-Sarmiento, Rogelio ; Alonso-Lopez, Diego ; Rivas, Javier ; Garcia-Cenador, Begona ; Garcia-Criado, Javier ; Lee, Do ; Bowen, Benjamin ; Reindl, Wolfgang ; Northen, Trent ; Mao, Jian-Hua ; Perez-Losada, Jesus

Background : An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. Results : Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and behavior of ERRB2-positive breast cancers. Our [...]