A partir d'échantillons sanguins prélevés sur 452 patients atteints d'une leucémie lymphocytaire chronique et sur 54 patients atteints d'une lymphocytose monoclonale de type B, cette étude identifie notamment de fréquentes mutations dans des régions non codantes du génome en lien avec des anomalies d'épissage et un comportement agressif de la maladie

Non-coding recurrent mutations in chronic lymphocytic leukaemia

Puente, Xose S. ; Bea, Silvia ; Valdes-Mas, Rafael ; Villamor, Neus ; Gutierrez-Abril, Jesus ; Martin-Subero, Jose I. ; Munar, Marta ; Rubio-Perez, Carlota ; Jares, Pedro ; Aymerich, Marta ; Baumann, Tycho ; Beekman, Renee ; Belver, Laura ; Carrio, Anna ; Castellano, Giancarlo ; Clot, Guillem ; Colado, Enrique ; Colomer, Dolors ; Costa, Dolors ; Delgado, Julio ; Enjuanes, Anna ; Estivill, Xavier ; Ferrando, Adolfo A. ; Gelpi, Josep L. ; Gonzalez, Blanca ; Gonzalez, Santiago ; González, Marcos ; Gut, Marta ; Hernández-Rivas, Jesús M. ; Lopez-Guerra, Monica ; Martin-Garcia, David ; Navarro, Alba ; Nicolas, Pilar ; Orozco, Modesto ; Payer, Angel R. ; Pinyol, Magda ; Pisano, David G. ; Puente, Diana A. ; Queiros, Ana C. ; Quesada, Victor ; Romeo-Casabona, Carlos M. ; Royo, Cristina ; Royo, Romina ; Rozman, Maria ; Russinol, Nuria ; Salaverria, Itziar ; Stamatopoulos, Kostas ; Stunnenberg, Hendrik G. ; Tamborero, David ; Terol, Maria J. ; Valencia, Alfonso ; Lopez-Bigas, Nuria ; Torrents, David ; Gut, Ivo ; Lopez-Guillermo, Armando ; López-Otín, Carlos ; Campo, Elias

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including [...]

Menée sur des lignées cellulaires de lymphome hodgkinien classique, cette étude identifie la présence fréquente de mutations inactivant l'expression du gène CD58

Alterations of the CD58 gene in classical Hodgkin lymphoma

Schneider, Markus ; Schneider, Stefanie ; Zühlke-Jenisch, Reina ; Klapper, Wolfram ; Sundstrom, Christer ; Hartmann, Sylvia ; Hansmann, Martin-Leo ; Siebert, Reiner ; Küppers, Ralf ; Giefing, Maciej

Immune evasion plays a central role in the pathophysiology of classical Hodgkin lymphoma (cHL). As mutations of the CD58 gene contribute to immune evasion of diffuse large B cell lymphoma tumor cells, we studied whether alterations of the CD58 gene also occur in Hodgkin and Reed/Sternberg (HRS) cells of cHL. Single nucleotide polymorphism chip analysis revealed homozygous deletions within the CD58 gene in two cHL cell lines (SUP-HD1 and U-HO1). Sequencing of the CD58 gene in seven cHL cell [...]

Menée initialement à partir d'échantillons tumoraux prélevés sur 25 patients atteints d'un lymphome NK/T, puis sur une cohorte complémentaire de 80 patients, cette étude chinoise identifie notamment de fréquentes mutations dans le gène DDX3X, en association avec un pronostic défavorable

Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma

Jiang, Lu ; Gu, Zhao-Hui ; Yan, Zi-Xun ; Zhao, Xia ; Xie, Yin-Yin ; Zhang, Zi-Guan ; Pan, Chun-Ming ; Hu, Yuan ; Cai, Chang-Ping ; Dong, Ying ; Huang, Jin-Yan ; Wang, Li ; Shen, Yang ; Meng, Guoyu ; Zhou, Jian-Feng ; Hu, Jian-Da ; Wang, Jin-Fen ; Liu, Yuan-Hua ; Yang, Lin-Hua ; Zhang, Feng ; Wang, Jian-Min ; Wang, Zhao ; Peng, Zhi-Gang ; Chen, Fang-Yuan ; Sun, Zi-Min ; Ding, Hao ; Shi, Ju-Mei ; Hou, Jian ; Yan, Jin-Song ; Shi, Jing-Yi ; Xu, Lan ; Li, Yang ; Lu, Jing ; Zheng, Zhong ; Xue, Wen ; Zhao, Wei-Li ; Chen, Zhu ; Chen, Sai-Juan

Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56+ and cytoCD3+ lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA [...]

A partir d'échantillons sanguins prélevés sur 40 patients atteints d'un lymphome T cutané, cette étude identifie 17 gènes présentant des mutations impliquées dans le développement de la maladie

Genomic landscape of cutaneous T cell lymphoma

Choi, Jaehyuk ; Goh, Gerald ; Walradt, Trent ; Hong, Bok S. ; Bunick, Christopher G. ; Chen, Kan ; Bjornson, Robert D. ; Maman, Yaakov ; Wang, Tiffany ; Tordoff, Jesse ; Carlson, Kacie ; Overton, John D. ; Liu, Kristina J. ; Lewis, Julia M. ; Devine, Lesley ; Barbarotta, Lisa ; Foss, Francine M. ; Subtil, Antonio ; Vonderheid, Eric C. ; Edelson, Richard L. ; Schatz, David G. ; Boggon, Titus J. ; Girardi, Michael ; Lifton, Richard P.

Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NF-[kappa]B signaling, chromatin remodeling and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations [...]

Menée à l'aide de 30 paires d'échantillons prélevés sur des patients ayant développé un adénocarcinome de l'oesophage à partir d'un endobrachyoesophage, cette étude suggère que le développement d'un adénocarcinome ne résulte généralement pas d'une accumulation graduelle d'anomalies dans des gènes suppresseurs de tumeurs

Paired exome analysis of Barrett's esophagus and adenocarcinoma

Stachler, Matthew D. ; Taylor-Weiner, Amaro ; Peng, Shouyong ; McKenna, Aaron ; Agoston, Agoston T. ; Odze, Robert D. ; Davison, Jon M. ; Nason, Katie S. ; Loda, Massimo ; Leshchiner, Ignaty ; Stewart, Chip ; Stojanov, Petar ; Seepo, Sara ; Lawrence, Michael S. ; Ferrer-Torres, Daysha ; Lin, Jules ; Chang, Andrew C. ; Gabriel, Stacey B. ; Lander, Eric S. ; Beer, David G. ; Getz, Gad ; Carter, Scott L. ; Bass, Adam J.

Barrett's esophagus is thought to progress to esophageal adenocarcinoma (EAC) through a stepwise progression with loss of CDKN2A followed by TP53 inactivation and aneuploidy. Here we present whole-exome sequencing from 25 pairs of EAC and Barrett's esophagus and from 5 patients whose Barrett's esophagus and tumor were extensively sampled. Our analysis showed that oncogene amplification typically occurred as a late event and that TP53 mutations often occurred early in Barrett's esophagus [...]

Menée à l'aide de 23 paires d'échantillons prélevés sur des patients ayant développé un adénocarcinome de l'oesophage à partir d'un endobrachyoesophage, cette étude de séquençage du génome entier met en évidence une hétérogénéité clonale et l'évolution du spectre des mutations entre les deux stades de la maladie

Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma

Ross-Innes, Caryn S. ; Becq, Jennifer ; Warren, Andrew ; Cheetham, R. Keira ; Northen, Helen ; O'Donovan, Maria ; Malhotra, Shalini ; di Pietro, Massimiliano ; Ivakhno, Sergii ; He, Miao ; Weaver, Jamie M. J. ; Lynch, Andy G. ; Kingsbury, Zoya ; Ross, Mark ; Humphray, Sean ; Bentley, David ; Fitzgerald, Rebecca C. ; for the Oesophageal Cancer, Clinical ; Molecular Stratification Study, Group

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and [...]

Menée sur des lignées cellulaires de leucémie avec réarrangements MLL, cette étude met en évidence des mécanismes par lesquels une histone déméthylase, KDM5B, régule les cellules souches leucémiques

The H3K4-Methyl Epigenome Regulates Leukemia Stem Cell Oncogenic Potential

Wong, Stephen H K. ; Goode, David L ; Iwasaki, Masayuki ; Wei, Michael C ; Kuo, Hsu-Ping ; Zhu, Li ; Schneidawind, Dominik ; Duque-Afonso, Jesus ; Weng, Ziming ; Cleary, Michael L

The genetic programs that maintain leukemia stem cell (LSC) self-renewal and oncogenic potential have been well defined; however, the comprehensive epigenetic landscape that sustains LSC cellular identity and functionality is less well established. We report that LSCs in MLL-associated leukemia reside in an epigenetic state of relative genome-wide high-level H3K4me3 and low-level H3K79me2. LSC differentiation is associated with reversal of these broad epigenetic profiles, with concomitant [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la perte du gène CDKN2B favorise l'évolution d'un nævus mélanocytaire bénin en mélanome

CDKN2B loss promotes progression from benign melanocytic nevus to melanoma

McNeal, Andrew S. ; Liu, Kevin ; Nakhate, Vihang ; Natale, Christopher A. ; Duperret, Elizabeth K. ; Capell, Brian C. ; Dentchev, Tzvete ; Berger, Shelley L. ; Herlyn, Meenhard ; Seykora, John T. ; Ridky, Todd W.

Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in benign melanocytic nevi, contributes to maintaining nevus melanocytes in a growth-arrested premalignant state, and is commonly [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la perte d'expression du gène RACK1 favorise le processus métastatique d'une tumeur gastrique

Loss of RACK1 promotes metastasis of gastric cancer by inducing a miRNA-302c / IL-8 signaling loop

Chen, Ling ; Min, Lingqiang ; Wang, Xuefei ; Zhao, Junjie ; Chen, Hua ; Qin, Jing ; Chen, Weidong ; Shen, Zhenbin ; Tang, Zhaoqing ; Gan, Qiangjun ; Ruan, Yuanyuan ; Sun, Yihong ; Qin, Xinyu ; Gu, Jianxin

Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and invasion and metastasis of gastric cancer represent the major reason for its poor prognosis. In this study, we found that loss of the receptor for activated C-kinase 1 (RACK1) promoted the metastasis of gastric cancer by enhancing the autocrine of interleukin (IL)-8 in vitro and in vivo. MicroRNA array identified that RACK1 modulated the expression of a series of microRNAs including microRNA-302 cluster, [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le micro ARN miR-224 favorise la progression d'une tumeur de cancer du poumon non à petites cellules

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

Cui, Ri ; Meng, Wei ; Sun, Hui-Lung ; Kim, Taewan ; Ye, Zhenqing ; Fassan, Matteo ; Jeon, Young-Jun ; Li, Bin ; Vicentini, Caterina ; Peng, Yong ; Lee, Tae Jin ; Luo, Zhenghua ; Liu, Lan ; Xu, Dongyuan ; Tili, Esmerina ; Jin, Victor ; Middleton, Justin ; Chakravarti, Arnab ; Lautenschlaeger, Tim ; Croce, Carlo M.

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, [...]

Cet article présente un modèle évolutionniste, intégrant les dynamiques d'interaction entre les cellules affectées par des mutations oncogéniques et leur micro-environnement, pour rendre compte de l'augmentation de l'incidence des cancers en fonction de l'âge

Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations

Rozhok, Andrii I. ; DeGregori, James

Our understanding of cancer has greatly advanced since Nordling [Nordling CO (1953) Br J Cancer 7(1):68–72] and Armitage and Doll [Armitage P, Doll R (1954) Br J Cancer 8(1):1–12] put forth the multistage model of carcinogenesis. However, a number of observations remain poorly understood from the standpoint of this paradigm in its contemporary state. These observations include the similar age-dependent exponential rise in incidence of cancers originating from stem/progenitor pools differing [...]

Cet article passe en revue les travaux récents sur l'intérêt d'une approche évolutionniste pour analyser les processus de développement d'un cancer et de la résistance aux traitements

Evolutionary Determinants of Cancer

Greaves, Mel

Our understanding of cancer is being transformed by exploring clonal diversity, drug resistance, and causation within an evolutionary framework. The therapeutic resilience of advanced cancer is a consequence of its character as a complex, dynamic, and adaptive ecosystem engendering robustness, underpinned by genetic diversity and epigenetic plasticity. The risk of mutation-driven escape by self-renewing cells is intrinsic to multicellularity but is countered by multiple restraints, facilitating [...]

Cet article passe en revue les travaux récents sur les caractéristiques biologiques d'une leucémie aiguë mégacaryoblastique

The biology of pediatric acute megakaryoblastic leukemia

Gruber, Tanja A. ; Downing, James R.

Acute Megakaryoblastic Leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) that morphologically resembles abnormal megakaryoblasts. While extremely rare in adults, pediatric cases comprise between 4 and 15% of newly diagnosed AML patients. AMKL in children with Down syndrome (DS) is characterized by a founding GATA1 mutation that cooperates with trisomy 21, followed by the acquisition of additional somatic mutations in epigenetic and kinase signaling genes. Clinically this manifests as [...]