A partir d'échantillons sanguins prélevés sur 4 219 participants, cette étude met en évidence la présence, croissante en fonction de l'âge, de mutations dans des gènes associés à une leucémie

Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis

McKerrell, Thomas ; Park, Naomi ; Moreno, Thaidy ; Grove, Carolyn S ; Ponstingl, Hannes ; Stephens, Jonathan ; Crawley, Charles ; Craig, Jenny ; Scott, Mike A ; Hodkinson, Clare ; Baxter, Joanna ; Rad, Roland ; Forsyth, Duncan R ; Quail, Michael A ; Zeggini, Eleftheria ; Ouwehand, Willem ; Varela, Ignacio ; Vassiliou, George S

Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were [...]

Menée sur 85 patients pédiatriques atteints d'une leucémie lymphoblastique aiguë (dont 67 avec réarrangements MLL), cette étude identifie un ensemble de mutations somatiques, en fonction de l'âge des patients et de la présence de réarrangements MLL

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

Andersson, Anna K. ; Ma, Jing ; Wang, Jianmin ; Chen, Xiang ; Gedman, Amanda Larson ; Dang, Jinjun ; Nakitandwe, Joy ; Holmfeldt, Linda ; Parker, Matthew ; Easton, John ; Huether, Robert ; Kriwacki, Richard ; Rusch, Michael ; Wu, Gang ; Li, Yongjin ; Mulder, Heather ; Raimondi, Susana ; Pounds, Stanley ; Kang, Guolian ; Shi, Lei ; Becksfort, Jared ; Gupta, Pankaj ; Payne-Turner, Debbie ; Vadodaria, Bhavin ; Boggs, Kristy ; Yergeau, Donald ; Manne, Jayanthi ; Song, Guangchun ; Edmonson, Michael ; Nagahawatte, Panduka ; Wei, Lei ; Cheng, Cheng ; Pei, Deqing ; Sutton, Rosemary ; Venn, Nicola C. ; Chetcuti, Albert ; Rush, Amanda ; Catchpoole, Daniel ; Heldrup, Jesper ; Fioretos, Thoas ; Lu, Charles ; Ding, Li ; Pui, Ching-Hon ; Shurtleff, Sheila ; Mullighan, Charles G. ; Mardis, Elaine R. ; Wilson, Richard K. ; Gruber, Tanja A. ; Zhang, Jinghui ; Downing, James R. ; for The St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome, Project

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of [...]

A partir d'échantillons tumoraux prélevés sur 60 patientes atteintes d'un cancer séreux ovarien de haut grade, puis menée sur des lignées cellulaires, cette étude identifie la présence d'une fusion des gènes BCAM et AKT2 chez 7% des patientes, puis met en évidence la fonction oncogénique de la protéine issue de cette fusion

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Kannan, Kalpana ; Coarfa, Cristian ; Chao, Pei-Wen ; Luo, Liming ; Wang, Yan ; Brinegar, Amy E. ; Hawkins, Shannon M. ; Milosavljevic, Aleksandar ; Matzuk, Martin M. ; Yen, Laising

High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Here we report a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. [...]

A partir de plusieurs échantillons de tissu tumoral et de tissu sain prélevés sur 3 patients atteints d'un cancer multifocal de la prostate, cette étude dresse l'arbre phylogénétique des populations cellulaires et met en évidence plusieurs expansions clonales

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue

Cooper, Colin S. ; Eeles, Rosalind ; Wedge, David C. ; Van Loo, Peter ; Gundem, Gunes ; Alexandrov, Ludmil B. ; Kremeyer, Barbara ; Butler, Adam ; Lynch, Andrew G. ; Camacho, Niedzica ; Massie, Charlie E. ; Kay, Jonathan ; Luxton, Hayley J. ; Edwards, Sandra ; Kote-Jarai, Zsofia ; Dennis, Nening ; Merson, Sue ; Leongamornlert, Daniel ; Zamora, Jorge ; Corbishley, Cathy ; Thomas, Sarah ; Nik-Zainal, Serena ; O'Meara, Sarah ; Matthews, Lucy ; Clark, Jeremy ; Hurst, Rachel ; Mithen, Richard ; Bristow, Robert G. ; Boutros, Paul C. ; Fraser, Michael ; Cooke, Susanna ; Raine, Keiran ; Jones, David ; Menzies, Andrew ; Stebbings, Lucy ; Hinton, Jon ; Teague, Jon ; McLaren, Stuart ; Mudie, Laura ; Hardy, Claire ; Anderson, Elizabeth ; Joseph, Olivia ; Goody, Victoria ; Robinson, Ben ; Maddison, Mark ; Gamble, Stephen ; Greenman, Christopher ; Berney, Dan ; Hazell, Steven ; Livni, Naomi ; the, Icgc Prostate Group ; Fisher, Cyril ; Ogden, Christopher ; Kumar, Pardeep ; Thompson, Alan ; Woodhouse, Christopher ; Nicol, David ; Mayer, Erik ; Dudderidge, Tim ; Shah, Nimish C. ; Gnanapragasam, Vincent ; Voet, Thierry ; Campbell, Peter ; Futreal, Andrew ; Easton, Douglas ; Warren, Anne Y. ; Foster, Christopher S. ; Stratton, Michael R. ; Whitaker, Hayley C. ; McDermott, Ultan ; Brewer, Daniel S. ; Neal, David E.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational [...]

A partir de 216 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un cancer colorectal (60 adénomes, 156 carcinomes), cette étude identifie des profils d'anomalies chromosomiques différents selon le type de cancer

Single nucleotide polymorphism array profiling identifies distinct chromosomal aberration patterns across colorectal adenomas and carcinomas

Zarzour, Peter ; Boelen, Lies ; Luciani, Fabio ; Beck, Dominik ; Sakthianandeswaren, Anuratha ; Mouradov, Dmitri ; Sieber, Oliver M. ; Hawkins, Nicholas J. ; Hesson, Luke B. ; Ward, Robyn L. ; Wong, Jason W. H.

The progression of benign colorectal adenomas into cancer is associated with the accumulation of chromosomal aberrations. Even though patterns and frequencies of chromosomal aberrations have been well established in colorectal carcinomas, corresponding patterns of aberrations in adenomas are less well documented. The aim of this study was to profile chromosomal aberrations across colorectal adenomas and carcinomas to provide a better insight into key changes during tumor initiation and [...]

Menée sur des lignées cellulaires et à l'aide d'un modèle murin de cancer du sein, cette étude met en évidence une hétérogénéité des populations cellulaires à l'intérieur des tumeurs

Intratumoral heterogeneity in a p53 null mouse model of human breast cancer

Zhang, Mei ; Tsimelzon, Anna ; Chang, Chi-Hsuan ; Fan, Cheng ; Wolff, Andrew ; Perou, Charles M. ; Hilsenbeck, Susan G. ; Rosen, Jeffrey M.

Intratumoral heterogeneity correlates with clinical outcome and reflects the cellular complexity and dynamics within a tumor. Such heterogeneity is thought to contribute to radio- and chemoresistance since many treatments may only target certain tumor cell subpopulations. A better understanding of the functional interactions between various subpopulations of cells, therefore, may help in the development of effective cancer treatments. We identified a unique subpopulation of tumor cells [...]

Menée à l'aide d'une technique de séquençage du génome entier à partir d'échantillons de la tumeur primitive et de trois tumeurs récidivantes prélevés sur une patiente atteinte d'un glioblastome, cette étude met en évidence l'évolution des mutations entre la tumeur primitive et les tumeurs récidivantes, notamment la disparition d'une mutation du gène IDH1 et l'apparition d'un minuscule chromosome double

Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macroevolution of a double minute chromosome

Favero, Francesco ; McGranahan, Nicholas ; Salm, Maximilian ; Birkbak, Nicolai J. ; Sanborn, J. Zachary ; Benz, Stephen C. ; Becq, Jennifer ; Peden, John F. ; Kingsbury, Zoya ; Grocok, Russell J. ; Humphray, Sean ; Bentley, David ; Spencer-Dene, Bradley ; Gutteridge, Alice ; Brada, Michael ; Roger, Stupp ; Dietrich, Pierre-Yves ; Forshew, Tim ; Gerlinger, Marco ; Rowan, Andrew ; Stamp, Gordon ; Eklund, Aron C. ; Szallasi, Zoltan ; Swanton, Charles

Background Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. Methods We describe a 35 year-old female patient with recurrent GBM following surgical removal of the primary tumor, adjuvant treatment with temozolomide, and a 3-year disease-free period. [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la kinase RIP1 favorise le développement d'un mélanome

RIP1 kinase is an oncogenic driver in melanoma

Liu, Xiao Ying ; Lai, Fritz ; Yan, Xu Guang ; Jiang, Chen Chen ; Guo, Su Tang ; Wang, Chun Yan ; Croft, Amanda ; Tseng, Hsin-Yi ; Wilmott, James S ; Scolyer, Richard A. ; Jin, Lei ; Zhang, Xu Dong

Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here we report that RIP1 functions as an oncogenic driver in human melanoma. While RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels le gène MIG6 exerce une fonction de suppresseur de tumeurs dans les adénocarcinomes du poumon présentant un gène EGFR muté

Loss of Mig6 accelerates initiation and progression of mutant Epidermal growth factor receptor-driven lung adenocarcinoma

Maity, Tapan K. ; Venugopalan, Abhilash ; Linnoila, Ilona ; Cultraro, Constance M. ; Giannakou, Andreas ; Nemati, Roxanne ; Zhang, Xu ; Webster, Joshua D. ; Ritt, Daniel ; Ghosal, Sarani ; Hoschuetzky, Heinz ; Simpson, R. Mark ; Biswas, Romi ; Politi, Katerina ; Morrison, Deborah K. ; Varmus, Harold E. ; Guha, Udayan

Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here we demonstrate that Mig6 is a tumor suppressor for the initiation and progression of mutant EGFR-driven lung adenocarcinoma in mouse models. Mutant EGFR-induced lung tumor formation was accelerated in Mig6-deficient mice, even with Mig6 [...]

Menée à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels la signalisation STAT3 exerce une fonction inattendue de suppresseur de tumeurs dans les adénocarcinomes du poumon présentant un gène KRAS muté

Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

Grabner, Beatrice ; Schramek, Daniel ; Mueller, Kristina M. ; Moll, Herwig P. ; Svinka, Jasmin ; Hoffmann, Thomas ; Bauer, Eva ; Blaas, Leander ; Hruschka, Natascha ; Zboray, Katalin ; Stiedl, Patricia ; Nivarthi, Harini ; Bogner, Edith ; Gruber, Wolfgang ; Mohr, Thomas ; Zwick, Ralf Harun ; Kenner, Lukas ; Poli, Valeria ; Aberger, Fritz ; Stoiber, Dagmar ; Egger, Gerda ; Esterbauer, Harald ; Zuber, Johannes ; Moriggl, Richard ; Eferl, Robert ; Gyorffy, Balázs ; Penninger, Josef M. ; Popper, Helmut ; Casanova, Emilio

STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de p53, le gène DBC1 exerce une fonction de suppresseur de tumeurs dans les cancers du sein

DBC1 Functions as a Tumor Suppressor by Regulating p53 Stability

Qin, Bo ; Minter-Dykhouse, Katherine ; Yu, Jia ; Zhang, Jun ; Liu, Tongzheng ; Zhang, Haoxing ; Lee, SeungBaek ; Kim, JungJin ; Wang, Liewei ; Lou, Zhenkun

DBC1 (deleted in breast cancer 1), also known as CCAR2 or KIAA1967, is an important negative regulator of SIRT1 and cellular stress response. Although the Dbc1 gene localizes at a region that is homozygously deleted in breast cancer, its role in tumorigenesis remains unclear. It has been suggested to be either a tumor suppressor or an oncogene. Therefore, the function of DBC1 in cancer needs to be further explored. Here, we report that Dbc1 knockout mice are tumor prone, suggesting that DBC1 [...]

Menée à l'ide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en activant une voie de signalisation de réparation de l'ADN, la protéine AKT3 favorise la progression d'un gliome et la résistance thérapeutique

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

Turner, Kristen M. ; Sun, Youting ; Ji, Ping ; Granberg, Kirsi J. ; Bernard, Brady ; Hu, Limei ; Cogdell, David E. ; Zhou, Xinhui ; Yli-Harja, Olli ; Nykter, Matti ; Shmulevich, Ilya ; Yung, W. K. Alfred ; Fuller, Gregory N. ; Zhang, Wei

Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un cancer (côlon, mélanome), cette étude met en évidence le rôle joué par l'enzyme IDH3 alpha dans la régulation des fibroblastes associés au cancer

Metabolic Reprogramming of Cancer-Associated Fibroblasts by IDH3α Downregulation

Zhang, Daoxiang ; Wang, Yongbin ; Shi, Zhimin ; Liu, Jingyi ; Sun, Pan ; Hou, Xiaodan ; Zhang, Jian ; Zhao, Shimin ; Zhou, Binhua P ; Mi, Jun

Cancer-associated fibroblasts (CAFs) provide critical metabolites for tumor growth and undergo metabolic reprogramming to support glycolysis. However, the molecular mechanisms responsible for this change remain unclear. Here, we report that TGF-?1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis. We identify downregulation of isocitrate dehydrogenase 3α (IDH3α) as a marker for this switch. Furthermore, miR-424 downregulates IDH3α during CAF formation. [...]

Cet article évalue l'intérêt d'un modèle simple de croissance tumorale pour rendre compte de la structure sous-clonale des tumeurs

Concepts in solid tumor evolution

Sidow, Arend ; Spies, Noah

Evolutionary mechanisms in cancer progression give tumors their individuality. Cancer evolution is different from organismal evolution, however, and we discuss where concepts from evolutionary genetics are useful or limited in facilitating an understanding of cancer. Based on these concepts we construct and apply the simplest plausible model of tumor growth and progression. Simulations using this simple model illustrate the importance of stochastic events early in tumorigenesis, highlight the [...]