A partir d'échantillons tumoraux prélevés sur deux cohortes de 28 et 274 patients atteints d'une tumeur épithéliale du thymus, cette étude identifie la présence fréquente d'une mutation du gène GTF2I

A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors

Petrini, Iacopo ; Meltzer, Paul S. ; Kim, In-Kyu ; Lucchi, Marco ; Park, Kang-Seo ; Fontanini, Gabriella ; Gao, James ; Zucali, Paolo A. ; Calabrese, Fiorella ; Favaretto, Adolfo ; Rea, Federico ; Rodriguez-Canales, Jaime ; Walker, Robert L. ; Pineda, Marbin ; Zhu, Yuelin J. ; Lau, Christopher ; Killian, Keith J. ; Bilke, Sven ; Voeller, Donna ; Dakshanamurthy, Sivanesan ; Wang, Yisong ; Giaccone, Giuseppe

We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I [...]

A partir d'échantillons prélevés sur 110 patients atteints d'une leucémie myéloïde aiguë présentant une translocation t(8;21), cette étude française identifie la présence fréquente de mutations somatiques du gène ASXL2 et évalue l'association entre la présence de mutations des gènes ASXL1 ou ASXL2 et le risque de récidive

Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations

Micol, Jean-Baptiste ; Duployez, Nicolas ; Boissel, Nicolas ; Petit, Arnaud ; Geffroy, Sandrine ; Nibourel, Olivier ; Lacombe, Catherine ; Lapillonne, Helene ; Etancelin, Pascaline ; Figeac, Martin ; Renneville, Aline ; Castaigne, Sylvie ; Leverger, Guy ; Ifrah, Norbert ; Dombret, Hervé ; Preudhomme, Claude ; Abdel-Wahab, Omar ; Jourdan, Eric

Acute myeloid leukemia (AML) with t(8;21)(q22;q22) is considered to have favorable risk however nearly half of t(8;21) patients are not cured and recent studies have highlighted remarkable genetic heterogeneity in this subset of AML. Here we identify somatic mutations in Additional Sex Combs-like 2 (ASXL2) in 22.7% (25/110) of patients with t(8;21) but not in inv(16)/t(16;16) (0/60) or RUNX1-mutated AML (0/26). ASXL2 mutations were similarly frequent in adult and pediatric t(8;21) and mutually [...]

Menée in vitro, cette étude suggère que deux mutations récemment identifiées dans le gène NTRK1 ne jouent pas un rôle causal dans le développement d'un mélanome

Functional characterization of NTRK1 mutations identified in melanoma

Miranda, Claudia ; Mazzoni, Mara ; Sensi, Marialuisa ; Pierotti, Marco A. ; Greco, Angela

Cutaneous melanoma is the most aggressive form of skin cancer, with a complex and heterogeneous aetiology. Deregulation of the mitogen activated protein kinase cascade is common in melanoma, due to activating mutations in the BRAF and NRAS genes. Genetic studies and high-throughput screening technologies have recently identified several somatic mutations affecting different receptor tyrosine kinase (RTK) genes. For the majority of these, however, the contribution to the complexity of melanoma [...]

Menée sur un patient atteint d'une tumeur interstitielle du poumon fœtal, cette étude met en évidence un réarrangement chromosomique impliquant une fusion des gènes ALK et A2M

Identification of novel ALK rearrangement A2M–ALK in a neonate with fetal lung interstitial tumor

Onoda, Tadashi ; Kanno, Miyako ; Sato, Hiroko ; Takahashi, Noriyuki ; Izumino, Hiroko ; Ohta, Hiroshi ; Emura, Takaki ; Katoh, Hirohisa ; Ohizumi, Hiroyuki ; Ohtake, Hiroya ; Asao, Hironobu ; Dehner, Louis P. ; Hill, Ashley D. ; Hayasaka, Kiyoshi ; Mitsui, Tetsuo

Fetal lung interstitial tumor (FLIT) is a recently reported type of congenital lung lesion comprising solid and cystic components. The pathological features include unique interstitial mesenchyme-based cell proliferation, and differ from other neoplasms represented by pleuropulmonary blastoma or congenital peribronchial myofibroblastic tumor. FLIT is extremely rare and its gene expression profile has not yet been reported. We provide the first report of a novel chromosomal rearrangement [...]

A partir d'une revue systématique de la littérature (10 articles identifiés, 5 599 patients au total), cette méta-analyse identifie les caractéristiques cliniques des patients atteints d'un cancer du poumon non à petites cellules présentant des mutations du gène BRAF

BRAF Mutations in Patients with Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Chen, Dong ; Zhang, Li-Qun ; Huang, Jun-Fu ; Liu, Kai ; Chuai, Zheng-Ran ; Yang, Zhao ; Wang, Yun-Xia ; Shi, Da-Chuan ; Liu, Qian ; Huang, Qing ; Fu, Wei-Ling

Background : BRAF mutations have been well described in non-small cell lung cancer (NSCLC) for several years, but the clinical features of patients harboring BRAF mutations are still not well described. We performed a meta-analysis to identify common clinical features in NSCLC patients carrying BRAF mutations. Methods : We identified clinical studies that examined the association between BRAF mutations and features of NSCLC within PubMed, Embase and ISI Science Citation Index database up to [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en agissant sur l'instabilité chromosomique, des anomalies de l'assemblage des microtubules sont susceptibles de favoriser la croissance tumorale d'un cancer colorectal

Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells

Ertych, Norman ; Stolz, Ailine ; Stenzinger, Albrecht ; Weichert, Wilko ; Kaulfuß, Silke ; Burfeind, Peter ; Aigner, Achim ; Wordeman, Linda ; Bastians, Holger

Chromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms influencing CIN and its consequences on tumour growth are largely unknown. We identified an increase in microtubule plus-end assembly rates as a mechanism influencing CIN in colorectal cancer cells. This phenotype is induced by overexpression of the oncogene AURKA or by loss of the tumour suppressor gene CHK2, a genetic [...]

Menée sur des lignées cellulaires et à partir de données issues du projet "The Cancer Genome Atlas", cette étude met en évidence des mécanismes par lesquels une instabilité chromosomique favorise la prolifération des cellules tumorales d'un cancer du sein ER+

Chromosomal instability selects gene copy number variants encoding core regulators of proliferation in ER+ breast cancer

Endesfelder, David ; Burrell, Rebecca ; Kanu, Nnennaya ; McGranahan, Nicholas ; Howell, Mike ; Parker, Peter J. ; Downward, Julian ; Swanton, Charles ; Kschischo, Maik

Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context-dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesised [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels le micro-ARN miR-124 exerce une fonction de suppresseur de tumeurs dans les ostéosarcomes

The Tumor Suppressor Role of miR-124 in Osteosarcoma

Geng, Shuo ; Zhang, Xiaojun ; Chen, Jie ; Liu, Xing ; Zhang, Hepeng ; Xu, Xiaoyan ; Ma, Yan ; Li, Baoxin ; Zhang, Yunqi ; Bi, Zhenggang ; Yang, Chenglin

MicroRNAs have crucial roles in development and progression of human cancers, including osteosarcoma. Recent studies have shown that miR-124 was down-regulated in many cancers; however, the role of miR-124 in osteosarcoma development is unkonwn. In this study, we demonstrate that expression of miR-124 is significantly downregulated in osteosarcoma tissues and cell lines, compared to the adjacent tissues. The expression of miR-124 in the metastases osteosarcoma tissues was lower than that in [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes d'interaction entre les gènes MTDH et SND1 favorisant la prolifération des cellules souches de cancer du sein

MTDH-SND1 Interaction Is Crucial for Expansion and Activity of Tumor-Initiating Cells in Diverse Oncogene- and Carcinogen-Induced Mammary Tumors

Wan, Liling ; Lu, Xin ; Yuan, Salina ; Wei, Yong ; Guo, Feng ; Shen, Minhong ; Yuan, Min ; Chakrabarti, Rumela ; Hua, Yuling ; Smith, Heath A ; Blanco, Mario Andres ; Chekmareva, Marina ; Wu, Hao ; Bronson, Roderick T ; Haffty, Bruce G ; Xing, Yongna ; Kang, Yibin

The Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis; however, its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH [...]

Menée à l'aide de modèles murins, cette étude met notamment en évidence des mécanismes par lesquels, en inhibant l'ostéoclastogenèse, le micro-ARN miR-34a réprime la formation de métastases osseuses d'un cancer du sein ou de la peau

miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2

Krzeszinski, Jing Y. ; Wei, Wei ; Huynh, HoangDinh ; Jin, Zixue ; Wang, Xunde ; Chang, Tsung-Cheng ; Xie, Xian-Jin ; He, Lin ; Mangala, Lingegowda S. ; Lopez-Berestein, Gabriel ; Sood, Anil K. ; Mendell, Joshua T. ; Wan, Yihong

Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease and present tremendous therapeutic potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing [...]

Menée sur des lignées cellulaires, des échantillons tumoraux et des modèles murins, cette étude met en évidence des mécanismes par lesquels, sous la régulation des gènes SXC10 et MYC, l'expression du gène RAB7 favorise la progression d'un mélanome

RAB7 Controls Melanoma Progression by Exploiting a Lineage-Specific Wiring of the Endolysosomal Pathway

Alonso-Curbelo, Direna ; Riveiro-Falkenbach, Erica ; Pérez-Guijarro, Eva ; Cifdaloz, Metehan ; Karras, Panagiotis ; Osterloh, Lisa ; Megías, Diego ; Cañón, Estela ; Calvo, Tonantzin G ; Olmeda, David ; Gómez-López, Gonzalo ; Graña, Osvaldo ; Sánchez-Arévalo Lobo, Víctor Javier ; Pisano, David G ; Wang, Hao-Wei ; Ortiz-Romero, Pablo ; Tormo, Damià ; Hoek, Keith ; Rodríguez-Peralto, José L ; Joyce, Johanna A ; Soengas, María S

Although common cancer hallmarks are well established, lineage-restricted oncogenes remain less understood. Here, we report an inherent dependency of melanoma cells on the small GTPase RAB7, identified within a lysosomal gene cluster that distinguishes this malignancy from over 35 tumor types. Analyses in human cells, clinical specimens, and mouse models demonstrated that RAB7 is an early-induced melanoma driver whose levels can be tuned to favor tumor invasion, ultimately defining metastatic [...]

Menée in vitro, in vivo et à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome du poumon, cette étude met en évidence le rôle joué par un récepteur des neurotrophines, TrkB, dans le processus métastatique

Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis

Sinkevicius, Kerstin W. ; Kriegel, Christina ; Bellaria, Kelly J. ; Lee, Jaewon ; Lau, Allison N. ; Leeman, Kristen T. ; Zhou, Pengcheng ; Beede, Alexander M. ; Fillmore, Christine M. ; Caswell, Deborah ; Barrios, Juliana ; Wong, Kwok-Kin ; Sholl, Lynette M. ; Schlaeger, Thorsten M. ; Bronson, Roderick T. ; Chirieac, Lucian R. ; Winslow, Monte M. ; Haigis, Marcia C. ; Kim, Carla F.

Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosin-related kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'expression du gène FN14 favorise la formation de métastases osseuses d'un cancer de la prostate résistant à la castration

AR-regulated TWEAK-FN14 Pathway Promotes Prostate Cancer Bone Metastasis

Yin, Juan Juan ; Liu, Yen-Nien ; Tillman, Heather ; Barrett, Ben ; Hewitt, Stephen ; Ylaya, Kris ; Fang, Lei ; Lake, Ross ; Corey, Eva ; Morrissey, Colm ; Vessella, Robert ; Kelly, Kathleen

The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKKβ-dependent, NFκB signaling activation. In human prostate cancer, upregulated FN14 expression was observed in greater than half of [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude met en évidence le rôle joué par le micro-ARN miR-409-3p/-5p dans la croissance tumorale, la transition épithélio-mésenchymateuse et la formation de métastases osseuses

miR-409-3p/-5p promotes tumorigenesis, epithelial to mesenchymal transition and bone metastasis of human prostate cancer

Josson, Sajni ; Gururajan, Murali ; Hu, Peizhen ; Shao, Chen ; Chu, Chia-Yi ; Zhau, Haiyen E ; Liu, Chunyan ; Lao, Kaiqin ; Lu, Chia-Lun ; Lu, Yi-Tsung ; Lichterman, Jake ; Nandana, Srinivas ; Li, Quanlin ; Rogatko, Andre ; Berel, Dror ; Posadas, Edwin M ; Fazli, Ladan ; Sareen, Dhruv ; Chung, Leland WK

Purpose: miR-409-3p/-5p is a microRNA expressed by embryonic stem cells and its role in cancer biology and metastasis is unknown. Our pilot studies demonstrated elevated miR-409-3p/-5p expression in human prostate cancer bone metastatic cell lines, therefore we defined the biological impact of manipulation of miR-409-3p/-5p in prostate cancer progression and correlated the levels of its expression with clinical human prostate cancer bone metastatic specimens. Experimental Design: miRNA [...]

Menée à l'aide de lignées cellulaires, cette étude met en évidence des mécanismes par lesquels un micro-ARN, miR-23b, favorise la dormance des cellules de cancer du sein dans une niche métastatique

Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells

Ono, Makiko ; Kosaka, Nobuyoshi ; Tominaga, Naoomi ; Yoshioka, Yusuke ; Takeshita, Fumitaka ; Takahashi, Ryou-u ; Yoshida, Masayuki ; Tsuda, Hitoshi ; Tamura, Kenji ; Ochiya, Takahiro

Breast cancer patients often develop metastatic disease years after resection of the primary tumor. The patients are asymptomatic because the disseminated cells appear to become dormant and are undetectable. Because the proliferation of these cells is slowed, dormant cells are often unresponsive to traditional chemotherapies that exploit the rapid cell cycling of most cancer cells. We generated a bone marrow–metastatic human breast cancer cell line (BM2) by tracking and isolating [...]

Menée sur des échantillons de sang périphérique, de la tumeur primitive et d'une métastase prélevés sur une patiente atteinte d'un cancer du sein, cette étude de séquençage de l'exome met en évidence la présence d'une perte d'homozygotie dans plusieurs régions chromosomiques du génome de la tumeur et de la métastase

A preliminary study of the relationship between breast cancer metastasis and loss of heterozygosity by using exome sequencing

Li, Hongsheng ; Yang, Bo ; Xing, Ke ; Yuan, Nangui ; Wang, Bo ; Chen, Zhenyu ; He, Weixing ; Zhou, Jie

We explored the feasibility of studying loss of heterozygosity (LOH) by using exome sequencing and compared the differences in genetic LOH between primary breast tumors and metastatic lesions. Exome sequencing was conducted to investigate the genetic LOH in the peripheral blood, a primary tumor, and a metastatic lesion from the same patient. LOH was observed in 30 and 48 chromosomal loci of the primary tumor and metastatic lesion, respectively. The incidence of LOH was the highest on chromosome [...]