A partir d'échantillons prélevés sur 99 patients atteints d'une leucémie aiguë mégacaryoblastique non liée à une trisomie 21 (75 patients pédiatriques, 24 adultes), cette étude identifie un ensemble d'anomalies génomiques permettant de définir sept sous-groupes de la maladie chez les enfants

Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes

de Rooij, Jasmijn D. E. ; Branstetter, Cristyn ; Ma, Jing ; Li, Yongjin ; Walsh, Michael P. ; Cheng, Jinjun ; Obulkasim, Askar ; Dang, Jinjun ; Easton, John ; Verboon, Lonneke J. ; Mulder, Heather L. ; Zimmermann, Martin ; Koss, Cary ; Gupta, Pankaj ; Edmonson, Michael ; Rusch, Michael ; Lim, Joshua Yew Suang ; Reinhardt, Katarina ; Pigazzi, Martina ; Song, Guangchun ; Yeoh, Allen Eng Juh ; Shih, Lee-Yung ; Liang, Der-Cherng ; Halene, Stephanie ; Krause, Diane S. ; Zhang, Jinghui ; Downing, James R. ; Locatelli, Franco ; Reinhardt, Dirk ; van den Heuvel-Eibrink, Marry M. ; Zwaan, C. Michel ; Fornerod, Maarten ; Gruber, Tanja A.

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4–15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene [...]

A partir de 26 échantillons de métastases prélevés sur 4 patients atteints d'un cancer du pancréas, cette étude met en évidence un faible degré d'hétérogénéité génétique entre les métastases d'un même patient

Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer

Makohon-Moore, Alvin P. ; Zhang, Ming ; Reiter, Johannes G. ; Bozic, Ivana ; Allen, Benjamin ; Kundu, Deepanjan ; Chatterjee, Krishnendu ; Wong, Fay ; Jiao, Yuchen ; Kohutek, Zachary A. ; Hong, Jungeui ; Attiyeh, Marc ; Javier, Breanna ; Wood, Laura D. ; Hruban, Ralph H. ; Nowak, Martin A. ; Papadopoulos, Nickolas ; Kinzler, Kenneth W. ; Vogelstein, Bert ; Iacobuzio-Donahue, Christine A.

The extent of heterogeneity among driver gene mutations present in naturally occurring metastases[mdash]that is, treatment-naive metastatic disease[mdash]is largely unknown. To address this issue, we carried out 60[times] whole-genome sequencing of 26 metastases from four patients with pancreatic cancer. We found that identical mutations in known driver genes were present in every metastatic lesion for each patient studied. Passenger gene mutations, which do not have known or predicted [...]

A partir d'échantillons tumoraux prélevés sur 509 patients atteints d'un cancer du poumon, cette étude analyse la prévalence des anomalies génomiques susceptibles d'induire la prescription d'une thérapie ciblée en fonction de l'origine ethnique des patients

Comparison of prevalence and types of mutations in lung cancers among black and white populations

Campbell, J. D. ; Lathan, C. ; Sholl, L. ; et al.,

Importance  Lung cancer is the leading cause of cancer death in the United States in all ethnic and racial groups. The overall death rate from lung cancer is higher in black patients than in white patients. Objective  To compare the prevalence and types of somatic alterations between lung cancers from black patients and white patients. Differences in mutational frequencies could illuminate differences in prognosis and lead to the reduction of outcome disparities by more precisely targeting [...]

A partir de données portant sur les réarrangements somatiques identifiés dans 560 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence 33 loci associés à de fréquentes duplications en tandem, puis suggère que certaines de ces mutations, parce qu'elles affectent des régions génomiques connues pour leur rôle de "super amplification", favorisent le développement du cancer

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Glodzik, Dominik ; Morganella, Sandro ; Davies, Helen ; Simpson, Peter T. ; Li, Yilong ; Zou, Xueqing ; Diez-Perez, Javier ; Staaf, Johan ; Alexandrov, Ludmil B. ; Smid, Marcel ; Brinkman, Arie B. ; Rye, Inga Hansine ; Russnes, Hege ; Raine, Keiran ; Purdie, Colin A. ; Lakhani, Sunil R. ; Thompson, Alastair M. ; Birney, Ewan ; Stunnenberg, Hendrik G. ; van de Vijver, Marc J. ; Martens, John W. M. ; Borresen-Dale, Anne-Lise ; Richardson, Andrea L. ; Kong, Gu ; Viari, Alain ; Easton, Douglas ; Evan, Gerard ; Campbell, Peter J. ; Stratton, Michael R. ; Nik-Zainal, Serena

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and [...]

A partir d'échantillons tumoraux prélevés sur 228 patientes atteintes d'un cancer primitif du col de l'utérus, cette étude identifie un ensemble d'anomalies génomiques et moléculaires et, notamment, une association entre des mutations des gènes KRAS, ARID1A et PTEN et un groupe de tumeurs non liées au papillomavirus humain

Integrated genomic and molecular characterization of cervical cancer

The Cancer Genome Atlas Research, Network

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, the largest comprehensive genomic study of cervical cancer to date. We observed striking APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered novel amplifications in immune targets CD274/PD-L1 and PDCD1LG2/PD-L2, and [...]

Menée sur des lignées cellulaires de myélome multiple, cette étude met en évidence des mécanismes par lesquels la kinase PAK4 exerce une fonction d'oncogène

Functional role and therapeutic targeting of p21-associated kinase 4 (PAK4) in multiple myeloma

Fulciniti, Mariateresa ; Martínez-López, Joaquin ; Senapedis, William ; Oliva, Stefania ; Bandi, Rajya Lakshmi ; Amodio, Nicola ; Xu, Yan ; Szalat, Raphael L. ; Gullà, Annamaria ; Samur, Mehmet K. ; Roccaro, Aldo ; Linares, Maria ; Cea, Michele ; Baloglu, Erkan ; Argueta, Christian ; Landesman, Yosef ; Shacham, Sharon ; Liu, Siyuan ; Schenone, Monica ; Wu, Shiaw-Lin ; Karger, Barry ; Prabhala, Rao ; Anderson, Kenneth C. ; Munshi, Nikhil C.

High expression of PAK4 promotes myeloma cell proliferation through activation of MM anti-apoptotic and survival pathways.Targeting PAK4 with a novel small molecule inhibitor, KPT-9274 has significant impact on MM cell growth and survival. Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of [...]

Menée in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la synthèse de l'ARN ribosomique, la protéine Ect2 favorise le développement d'un adénocarcinome du poumon

Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma

Justilien, Verline ; Ali, Syed A. ; Jamieson, Lee ; Yin, Ning ; Cox, Adrienne D. ; Der, Channing J. ; Murray, Nicole R. ; Fields, Alan P.

The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor [...]

Menée sur des lignées cellulaires de cancer du sein de type basal et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels la signalisation NOTCH3 favorise le développement d'une tumeur

Constitutive NOTCH3 signaling promotes the growth of basal breast cancers

Choy, Lisa ; Hagenbeek, Thijs ; Solon, Margaret ; French, Dorothy M. ; Finkle, David ; Shelton, Amy ; Venook, Rayna ; Brauer, Matthew J. ; Siebel, Christian W.

Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a [...]

Menée sur des lignées de cellules souches de cancer du sein, cette étude met en évidence le rôle joué par la protéine G3BP2 dans le développement initial d'une tumeur

Stress granule-associated protein G3BP2 regulates breast tumor initiation

Gupta, Nisha ; Badeaux, Mark ; Liu, Yiqian ; Naxerova, Kamila ; Sgroi, Dennis ; Munn, Lance L. ; Jain, Rakesh K. ; Garkavtsev, Igor

Breast tumors contain tumorigenic cancer cells, termed “tumor-initiating cells” (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. Here we describe a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We identified [...]

Menée à l'aide de modèles murins de cancer du sein surexprimant ErbB2, cette étude met en évidence des mécanismes par lesquels une haploinsuffisance du gène de la bêta-caténine favorise le développement d'une tumeur de type basal

Beta-Catenin haploinsufficiency promotes mammary tumorigenesis in an ErbB2-positive basal breast cancer model

Tung, Bui ; Schade, Babette ; Cardiff, Robert D. ; Aina, Olulanu H. ; Sanguin-Gendreau, Virginie ; Muller, William J.

Aberrant activation of β-catenin through its activity as a transcription factor has been observed in a large proportion of human malignancies. Despite the improved understanding of the β-catenin signaling pathway over the past three decades, attempts to develop therapies targeting β-catenin remain challenging, and none of these targeted therapies have advanced to the clinic. In this study, we show that part of the challenge in antagonizing β-catenin is caused by its dual functionality as a cell [...]

Menée in vitro et in vivo sur des modèles de cancer de l'ovaire, cette étude met en évidence des mécanismes par lesquels, en altérant la glycolyse dans les fibroblastes associés au cancer, un long ARN non codant (LINC00092) favorise le processus métastatique

Long non-coding RNA LINC00092 acts in cancer-associated fibroblasts to drive glycolysis and progression of ovarian cancer

Zhao, Linjie ; Ji, Gaili ; Le, Xiaobing ; Wang, Chenlu ; Xu, Lian ; Feng, Min ; Zhang, Yaguang ; Yang, Huiliang ; Xuan, Yu ; Yang, Yanfei ; Lei, Lingzi ; Yang, Qilian ; Lau, Wayne Bond ; Lau, Bonnie ; Chen, Yi ; Deng, Xiangbing ; Yao, Shaohua ; Yi, Tao ; Zhao, Xia ; Wei, Yuquan ; Zhou, Shengtao

The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when peritoneal metastases exist, however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long non-coding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Pro-metastatic properties of CAF in vitro and in vivo were found to associate with elevated expression of the chemokine [...]

A partir d'échantillons de tumeurs primitives et de métastases distantes prélevés à l'autopsie sur des patients atteints d'un adénocarcinome canalaire du pancréas, puis menée in vitro et in vivo, cette étude met en évidence des mécanimes de reprogrammation épigénomique de la chromatine au cours de l'évolution naturelle des métastases

Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis

McDonald, Oliver G. ; Li, Xin ; Saunders, Tyler ; Tryggvadottir, Rakel ; Mentch, Samantha J. ; Warmoes, Marc O. ; Word, Anna E. ; Carrer, Alessandro ; Salz, Tal H. ; Natsume, Sonoko ; Stauffer, Kimberly M. ; Makohon-Moore, Alvin ; Zhong, Yi ; Wu, Hao ; Wellen, Kathryn E. ; Locasale, Jason W. ; Iacobuzio-Donahue, Christine A. ; Feinberg, Andrew P.

During the progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death. However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones. This raises the possibility that an epigenetic process might operate during metastasis. Here we report large-scale reprogramming of chromatin [...]

Menée in vitro et in vivo sur des modèles d'adénocarcinome canalaire du pancréas, cette étude met en évidence des mécanismes de nature épigénétique par lesquels des interactions entre cellules du microenvironnement tumoral favorisent la croissance tumorale

Stromal cues regulate the pancreatic cancer epigenome and metabolome

Sherman, Mara H. ; Yu, Ruth T. ; Tseng, Tiffany W. ; Sousa, Cristovão M. ; Liu, Sihao ; Truitt, Morgan L. ; He, Nanhai ; Ding, Ning ; Liddle, Christopher ; Atkins, Annette R. ; Leblanc, Mathias ; Collisson, Eric A. ; Asara, John M. ; Kimmelman, Alec C. ; Downes, Michael ; Evans, Ronald M.

A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap [...]

A partir d'échantillons tumoraux prélevés sur 87 patients atteints d'un carcinome épidermoïde du poumon, puis menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels une surexpression de la protéine STXBP4 favorise la croissance tumorale

STXBP4 drives tumor growth and is associated with poor prognosis through PDGF Receptor signaling in lung squamous cell carcinoma

Otaka, Yukihiro ; Rokudai, Susumu ; Kaira, Kyoichi ; Fujieda, Michiru ; Horikoshi, Ikuko ; Kawabata, Reika ; Yoshiyama, Shinji ; Yokobori, Takehiko ; Ohtaki, Yoichi ; Shimizu, Kimihiro ; Oyama, Tetsunari ; Tamura, Jun ; ichi, ; Prives, Carol ; Nishiyama, Masahiko

Purpose: Expression of the ΔN isoform of p63 (ΔNp63) is a diagnostic marker highly specific for lung squamous cell carcinoma (SCC). We previously found that Syntaxin Binding Protein 4 (STXBP4) regulates ΔNp63 ubiquitination, suggesting that STXBP4 may also be a SCC biomarker. To address this issue, we investigated the role of STXBP4 expression in SCC biology and the impact of STXBP4 expression on SCC prognosis. Experimental design: We carried out a clinicopathological analysis of STXBP4 [...]

A partir d'échantillons tumoraux prélevés sur 107 patients atteints d'un cancer primitif du côlon-rectum de stade II-IV (dont 50% ont atteint le stade métastatique), puis menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels des mutations du récepteur de l'éphrine B favorisent le processus métastatique

Somatic ephrin receptor mutations are associated with metastasis in primary colorectal cancer

Mathot, Lucy ; Kundu, Snehangshu ; Ljungström, Viktor ; Svedlund, Jessica ; Moens, Lotte ; Adlerteg, Tom ; Falk-Sörqvist, Elin ; Rendo, Verónica ; Bellomo, Claudia ; Mayrhofer, Markus ; Cortina, Carme ; Sundström, Magnus ; Micke, Patrick ; Botling, Johan ; Isaksson, Anders ; Moustakas, Aristidis ; Batlle, Eduard ; Birgisson, Helgi ; Glimelius, Bengt ; Nilsson, Mats ; Sjöblom, Tobias

The contribution of somatic mutations to metastasis of colorectal cancers (CRC) is currently unknown. To find mutations involved in the CRC metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II-IV primary CRC, of which half had metastasized. The mutation prevalence in the ephrin (Eph) family of tyrosine kinase receptors was ten-fold higher in primary tumors of metastatic CRC than in non-metastatic cases and preferentially occurred in stage III and IV tumours. [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, dans des conditions d'hypoxie, des cellules cancéreuses porteuses du papillomavirus humain sont susceptibles d'entrer dans un stade de dormance

Induction of dormancy in hypoxic human papillomavirus-positive cancer cells

Hoppe-Seyler, Karin ; Bossler, Felicitas ; Lohrey, Claudia ; Bulkescher, Julia ; Rösl, Frank ; Jansen, Lars ; Mayer, Arnulf ; Vaupel, Peter ; Dürst, Matthias ; Hoppe-Seyler, Felix

Oncogenic human papillomaviruses (HPVs) are closely linked to major human malignancies, including cervical and head and neck cancers. It is widely assumed that HPV-positive cancer cells are under selection pressure to continuously express the viral E6/E7 oncogenes, that their intracellular p53 levels are reconstituted on E6/E7 repression, and that E6/E7 inhibition phenotypically results in cellular senescence. Here we show that hypoxic conditions, as are often found in subregions of cervical [...]

Menée in vitro et in vivo sur des modèles de cancer de la vessie, cette étude met en évidence des mécanismes par lesquels la voie de signalisation COX2/mPGES1/PGE2 régule l'expression de PD-L1 dans les cellules myéloïdes infiltrant les tumeurs

COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

Prima, Victor ; Kaliberova, Lyudmila N. ; Kaliberov, Sergey ; Curiel, David T. ; Kusmartsev, Sergei

In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)–mediated inhibition of activated PD-1+ T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti–PD-L1 and –PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine [...]