Menée initialement sur des échantillons de tissu tumoral et de tissu sain prélevés sur 13 patients atteints d'une leucémie myélomonocytaire juvénile, puis sur 92 échantillons tumoraux complémentaires, cette étude de séquençage de l'exome identifie des mutations secondaires des gènes SETBP1 et JAK3

Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia

Sakaguchi, Hirotoshi ; Okuno, Yusuke ; Muramatsu, Hideki ; Yoshida, Kenichi ; Shiraishi, Yuichi ; Takahashi, Mariko ; Kon, Ayana ; Sanada, Masashi ; Chiba, Kenichi ; Tanaka, Hiroko ; Makishima, Hideki ; Wang, Xinan ; Xu, Yinyan ; Doisaki, Sayoko ; Hama, Asahito ; Nakanishi, Koji ; Takahashi, Yoshiyuki ; Yoshida, Nao ; Maciejewski, Jaroslaw P. ; Miyano, Satoru ; Ogawa, Seishi ; Kojima, Seiji

Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases2. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes [...]

Menée sur des échantillons prélevés sur 727 patients atteints d'une forme de leucémie myéloïde, cette étude identifie la présence récurrente de mutations somatiques du gène SETBP1

Somatic SETBP1 mutations in myeloid malignancies

Makishima, Hideki ; Yoshida, Kenichi ; Nguyen, Nhu ; Przychodzen, Bartlomiej ; Sanada, Masashi ; Okuno, Yusuke ; Ng, Kwok Peng ; Gudmundsson, Kristbjorn O. ; Vishwakarma, Bandana A. ; Jerez, Andres ; Gomez-Segui, Ines ; Takahashi, Mariko ; Shiraishi, Yuichi ; Nagata, Yasunobu ; Guinta, Kathryn ; Mori, Hiraku ; Sekeres, Mikkael A. ; Chiba, Kenichi ; Tanaka, Hiroko ; Muramatsu, Hideki ; Sakaguchi, Hirotoshi ; Paquette, Ronald L. ; McDevitt, Michael A. ; Kojima, Seiji ; Saunthararajah, Yogen ; Miyano, Satoru ; Shih, Lee-Yung ; Du, Yang ; Ogawa, Seishi ; Maciejewski, Jaroslaw P.

Here we report whole-exome sequencing of individuals with various myeloid malignancies and identify recurrent somatic mutations in SETBP1, consistent with a recent report on atypical chronic myeloid leukemia (aCML)1. Closely positioned somatic SETBP1 mutations encoding changes in Asp868, Ser869, Gly870, Ile871 and Asp880, which match germline mutations in Schinzel-Giedion syndrome (SGS)2, were detected in 17% of secondary acute myeloid leukemias (sAML) and 15% of chronic myelomonocytic leukemia [...]

Menée sur des échantillons tumoraux prélevés sur 46 patients ayant développé un mélanome en association avec un nævus, cette étude montre que la présence d'une mutation du gène BRAF ou NRAS dans un nævus n'est pas associée au risque de transformation maligne

NRAS and BRAF Mutations in Melanoma-Associated Nevi and Uninvolved Nevi

Tschandl, Philipp ; Berghoff, Anna Sophie ; Preusser, Matthias ; Burgstaller-Muehlbacher, Sebastian ; Pehamberger, Hubert ; Okamoto, Ichiro ; Kittler, Harald

According to the prevailing multistep model of melanoma development, oncogenic BRAF or NRAS mutations are crucial initial events in melanoma development. It is not known whether melanocytic nevi that are found in association with a melanoma are more likely to carry BRAF or NRAS mutations than uninvolved nevi. By laser microdissection we were able to selectively dissect and genotype cells either from the nevus or from the melanoma part of 46 melanomas that developed in association with a nevus. [...]

Menée sur 34 échantillons tumoraux et échantillons de sang périphérique prélevés sur des patients atteints d'un mélanome cutané, cette étude met en évidence, pour les tumeurs dont les gènes BRAF et NRAS ne sont pas mutés, un taux élevé de mutations en association avec des lésions provoquées par une exposition aux rayonnements ultra-violets

BRAF/NRAS wild-type melanomas have a high mutation load correlating with histological and molecular signatures of UV damage

Mar, Victoria J. ; Wong, Stephen Q. ; Li, Jason ; Scolyer, Richard A. ; McLean, Catriona ; Papenfuss, Anthony T. ; Tothill, Richard W. ; Kakavand, Hojabr ; Mann, Graham J. ; Thompson, John F. ; Behren, Andreas ; Cebon, Jonathan S. ; Wolfe, Rory ; Kelly, John W. ; Dobrovic, Alex ; McArthur, Grant A.

Purpose: The mutation load in melanoma is generally high compared to other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinico-pathologic features. Experimental Design: DNA was extracted from 34 fresh frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was [...]

Menée sur des lignées cellulaires de cancer du poumon, cette étude identifie trois kinases, FGFR4, MAP3K9 et PAK5, affectées de mutations leur procurant un gain de fonctions dans la voie de signalisation ERK

Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer

Fawdar, Shameem ; Trotter, Eleanor W. ; Li, Yaoyong ; Stephenson, Natalie L. ; Hanke, Franziska ; Marusiak, Anna A. ; Edwards, Zoe C. ; Ientile, Sara ; Waszkowycz, Bohdan ; Miller, Crispin J. ; Brognard, John

Approximately 70% of patients with non–small-cell lung cancer present with late-stage disease and have limited treatment options, so there is a pressing need to develop efficacious targeted therapies for these patients. This remains a major challenge as the underlying genetic causes of ∼50% of non–small-cell lung cancers remain unknown. Here we demonstrate that a targeted genetic dependency screen is an efficient approach to identify somatic cancer alterations that are functionally important. [...]

Menée sur des échantillons tumoraux prélevés sur 883 patients atteints d'un cancer du poumon non à petites cellules, cette étude montre que des mutations du gène BRAF sont présentes chez 4% des patients et que 50% d'entre elles diffèrent de la mutation V600E

Clinical, pathological and biological features associated with BRAF mutations in non-small cell lung cancer

Cardarella, Stephanie ; Ogino, Atsuko ; Nishino, Mizuki ; Butaney, Mohit ; Shen, Jeanne ; Lydon, Christine ; Yeap, Beow Y. ; Sholl, Lynette ; Johnson, Bruce E. ; Jänne, Pasi A.

Purpose: BRAF mutations are found in a subset of non-small cell lung cancers (NSCLCs). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Experimental Design: Using DNA sequencing, we successfully screened 883 NSCLC patients for BRAF mutations between 7/1/09 and 7/16/12. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild type controls consisted of NSCLC patients [...]

Menée sur 4 lignées cellulaires et 16 échantillons tumoraux prélevés sur des patients atteints d'un carcinome à cellules rénales avec translocations impliquant les gènes TFEB et TFE3, cette étude met en évidence l'hétéréogénéité génomique de cette forme rare de cancer du rein

Genomic Heterogeneity of Translocation Renal Cell Carcinoma

Malouf, Gabriel G ; Monzon, Federico A ; COUTURIER, Jérôme ; Molinié, Vincent ; Escudier, Bernard ; Camparo, Philippe ; Su, Xiaoping ; Yao, Hui ; Tamboli, Pheroze ; Lopez-Terrada, Dolores ; Picken, Maria ; Varella-Garcia, Marileila ; Multani, Asha ; Pathak, Sen ; Wood, Christopher G ; Tannir, Nizar M.

Purpose: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney cancer involving the TFEB/TFE3 genes. We aimed to investigate the genomic and epigenetic features of this entity. Experimental design: Cytogenomic analysis was performed with 250K single-nucleotide polymorphism microarrays on 16 tumor specimens and 4 cell lines. LINE-1 methylation, a surrogate marker of DNA methylation, was performed on 27 cases using pyrosequencing. Results: tRCC showed cytogenomic heterogeneity, [...]

Cet article passe en revue les travaux récents sur la biologie moléculaire des tumeurs stromales gastro-intestinales ne présentant pas de mutation des gènes KIT ou PDGFRA

An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST)

Nannini, Margherita ; Biasco, Guido ; Astolfi, Annalisa ; Pantaleo, Maria A

Background About 85% of paediatric gastrointestinal stromal tumours (GISTs) and about 10–15% of adult GISTs do not harbour any mutations in the KIT and PDGFRA genes and are defined as KIT/PDGFRA wild type (WT). Over the years it has been demonstrated that KIT/PDGFRA WT GISTs are profoundly different from mutant GIST in clinical and molecular profiles, so that they are now considered a separate pathological entity. Moreover, due to their extreme molecular and clinical heterogeneity, KIT/PDGFRA [...]

Menée in vitro et sur 101 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence le rôle de suppresseur de tumeurs joué par le gène de l'horloge circadienne PER2

Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy

Hwang-Verslues, Wendy W. ; Chang, Po-Hao ; Jeng, Yung-Ming ; Kuo, Wen-Hung ; Chiang, Pei-Hsun ; Chang, Yi-Cheng ; Hsieh, Tsung-Han ; Su, Fang-Yi ; Lin, Liu-Chen ; Abbondante, Serena ; Yang, Cheng-Yuan ; Hsu, Huan-Ming ; Yu, Jyh-Cherng ; Chang, King-Jen ; Shew, Jin-Yuh ; Lee, Eva Y.-H. P. ; Lee, Wen-Hwa

The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of PER2 enhanced invasion and activated expression of epithelial-mesenchymal transition (EMT) genes including TWIST1, SLUG, and SNAIL. This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en ciblant le gène TET2, le micro-ARN 22 favorise le développement d'une leucémie

The Oncogenic MicroRNA miR-22 Targets the TET2 Tumor Suppressor to Promote Hematopoietic Stem Cell Self-Renewal and Transformation

Song, Su Jung ; Ito, Keisuke ; Ala, Ugo ; Kats, Lev ; Webster, Kaitlyn ; Sun, Su Ming ; Jongen-Lavrencic, Mojca ; Manova-Todorova, Katia ; Teruya-Feldstein, Julie ; Avigan, David E ; Delwel, Ruud ; Pandolfi, Pier Paolo

MicroRNAs are frequently deregulated in cancer. Here we show that miR-22 is upregulated in myelodysplastic syndrome (MDS) and leukemia and its aberrant expression correlates with poor survival. To explore its role in hematopoietic stem cell function and malignancy, we generated transgenic mice conditionally expressing miR-22 in the hematopoietic compartment. These mice displayed reduced levels of global 5-hydroxymethylcytosine (5-hmC) and increased hematopoietic stem cell self-renewal [...]

Cet article passe en revue les travaux récents sur les mécanismes moléculaires impliqués dans les tumeurs neuroendocrines du pancréas

Current Understanding of the Molecular Biology of Pancreatic Neuroendocrine Tumors

Zhang, Jianliang ; Francois, Rony ; Iyer, Renuka ; Seshadri, Mukund ; Zajac-Kaye, Maria ; Hochwald, Steven N.

Pancreatic neuroendocrine tumors (PanNETs) are complicated and often deadly neoplasms. A recent increased understanding of their molecular biology has contributed to expanded treatment options. DNA sequencing of samples derived from patients with PanNETs and rare genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Von Hippel–Lindau (VHL) syndrome reveals the involvement of MEN1, DAXX/ATRX, and the mammalian target of rapamycin (mTOR) pathways in PanNET tumorigenesis. Gene [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, via la régulation de la mitose, la kinase TBK1 favorise la survie des cellules de cancer du poumon

Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells

Kim, Jae-Young ; Welsh, Eric A. ; Oguz, Umut ; Fang, Bin ; Bai, Yun ; Kinose, Fumi ; Bronk, Crystina ; Remsing Rix, Lily L. ; Beg, Amer A. ; Rix, Uwe ; Eschrich, Steven A. ; Koomen, John M. ; Haura, Eric B.

TANK-binding kinase 1 (TBK1) has emerged as a novel therapeutic target for unspecified subset of lung cancers. TBK1 reportedly mediates prosurvival signaling by activating NF-κB and AKT. However, we observed that TBK1 knockdown also decreased viability of cells expressing constitutively active NF-κB and interferon regulatory factor 3. Basal phospho-AKT level was not reduced after TBK1 knockdown in TBK1-sensitive lung cancer cells, implicating that TBK1 mediates unknown survival mechanisms. To [...]

Menée à l'aide d'un modèle murin de cancer du côlon, cette étude met en évidence des mécanismes par lesquels le sulfure d'hydrogène produit par la synthase CBS favorise la croissance tumorale et l'angiogenèse

Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer

Szabo, Csaba ; Coletta, Ciro ; Chao, Celia ; Módis, Katalin ; Szczesny, Bartosz ; Papapetropoulos, Andreas ; Hellmich, Mark R.

The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H2S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS [...]

Menée sur des cellules de tissu normal du sein, cette étude montre que des cellules surexprimant p27 sont associées à un risque de cancer du sein, ce qui permet de rendre compte de l'effet protecteur d'une grossesse précoce sur la réduction de ce risque

Molecular Profiling of Human Mammary Gland Links Breast Cancer Risk to a p27+ Cell Population with Progenitor Characteristics

Choudhury, Sibgat ; Almendro, Vanessa ; Merino, Vanessa F ; Wu, Zhenhua ; Maruyama, Reo ; Su, Ying ; Martins, Filipe C ; Fackler, Mary Jo ; Bessarabova, Marina ; Kowalczyk, Adam ; Conway, Thomas ; Beresford-Smith, Bryan ; Macintyre, Geoff ; Cheng, Yu-Kang ; Lopez-Bujanda, Zoila ; Kaspi, Antony ; Hu, Rong ; Robens, Judith ; Nikolskaya, Tatiana ; Haakensen, Vilde D ; Schnitt, Stuart J ; Argani, Pedram ; Ethington, Gabrielle ; Panos, Laura ; Grant, Michael ; Clark, Jason ; Herlihy, William ; Lin, S.  Joyce ; Chew, Grace ; Thompson, Erik W ; Greene-Colozzi, April ; Richardson, Andrea L ; Rosson, Gedge D ; Pike, Malcolm ; Garber, Judy E ; Nikolsky, Yuri ; Blum, Joanne L ; Au, Alfred ; Hwang, E.  Shelley ; Tamimi, Rulla M ; Michor, Franziska ; Haviv, Izhak ; Liu, X.  Shirley ; Sukumar, Saraswati ; Polyak, Kornelia

Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44+ progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le promoteur du gène ZEB1 favorise l'induction d'un état de cellule souche cancéreuse dans des cellules de cancer du sein de type basal

Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity

Chaffer, Christine L ; Marjanovic, Nemanja D ; Lee, Tony ; Bell, George ; Kleer, Celina G ; Reinhardt, Ferenc ; D Alessio, Ana C ; Young, Richard A ; Weinberg, Robert A

The recent discovery that normal and neoplastic epithelial cells re-enter the stem cell state raised the intriguing possibility that the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs) but from their proclivity to generate new CSCs from non-CSC populations. Here, we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC state. The observed cell plasticity is dependent on [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par les pièges extracellulaires des neutrophiles dans le processus métastatique consécutif à une infection post-chirurgicale

Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis

Cools-Lartigue, Jonathan ; Spicer, Jonathan ; McDonald, Braedon ; Gowing, Stephen ; Chow, Simon ; Giannias, Betty ; Bourdeau, France ; Kubes, Paul ; Ferri, Lorenzo

The majority of patients with cancer undergo at least one surgical procedure as part of their treatment. Severe postsurgical infection is associated with adverse oncologic outcomes; however, the mechanisms underlying this phenomenon are unclear. Emerging evidence suggests that neutrophils, which function as the first line of defense during infections, facilitate cancer progression. Neutrophil extracellular traps (NETs) are extracellular neutrophil-derived DNA webs released in response to [...]

Menée à l'aide de modèles murins de mélanome, de cancer du côlon et du sein, cette étude met en évidence des mécanismes par lesquels, dans le micro-environnement tumoral, la signalisation du récepteur à activité tyrosine kinase MerTK favorise la croissance tumorale

MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis

Cook, Rebecca S. ; Jacobsen, Kristen M. ; Wofford, Anne M. ; DeRyckere, Deborah ; Stanford, Jamie ; Prieto, Anne L. ; Redente, Elizabeth ; Sandahl, Melissa ; Hunter, Debra M. ; Strunk, Karen E. ; Graham, Douglas K. ; Earp, H. Shelton, III

MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK–/– mice. Transplantation of MerTK–/– bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic [...]

Menée à l'aide de deux modèles murins, cette étude met en évidence le rôle joué par une petite population cellulaire, enrichie après une chimiothérapie, dans la propagation d'une tumeur de cancer du poumon non à petites cellules

A Rare Population of CD24+ITGB4+Notchhi Cells Drives Tumor Propagation in NSCLC and Requires Notch3 for Self-Renewal

Zheng, Yanyan ; de la Cruz, Cecile C ; Sayles, Leanne C ; Alleyne-Chin, Chris ; Vaka, Dedeepya ; Knaak, Tim D ; Bigos, Marty ; Xu, Yue ; Hoang, Chuong D ; Shrager, Joseph B ; Fehling, Hans Joerg ; French, Dorothy ; Forrest, William ; Jiang, Zhaoshi ; Carano, Richard A. D. ; Barck, Kai H. ; Jackson, Erica L ; Sweet-Cordero, E.  Alejandro

Sustained tumor progression has been attributed to a distinct population of tumor-propagating cells (TPCs). To identify TPCs relevant to lung cancer pathogenesis, we investigated functional heterogeneity in tumor cells isolated from Kras-driven mouse models of non-small-cell lung cancer (NSCLC). CD24+ITGB4+Notchhi cells are capable of propagating tumor growth in both a clonogenic and an orthotopic serial transplantation assay. While all four Notch receptors mark TPCs, Notch3 plays a [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation Jagged1/Notch, l'enzyme APEX1 favorise la progression d'un cancer du côlon

Colon cancer progression is driven by APEX1-mediated upregulation of Jagged

Kim, Mi-Hwa ; Kim, Hong-Beum ; Yoon, Sang Pil ; Lim, Sung-Chul ; Cha, Man Jin ; Jeon, Young Jin ; Park, Sang Gon ; Chang, In-Youb ; You, Ho Jin

Aberrant expression of apurinic-apyrimidinic endonuclease–1 (APEX1) has been reported in numerous human solid tumors and is positively correlated with cancer progression; however, the role of APEX1 in tumor progression is poorly defined. Here, we show that APEX1 contributes to aggressive colon cancer behavior and functions as an upstream activator in the Jagged1/Notch signaling pathway. APEX1 overexpression or knockdown in human colon cancer cell lines induced profound changes in malignant [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en induisant une transition épithélio-mésenchymateuse, le micro-ARN 22 favorise le processus métastatique d'un cancer du sein

MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family-Dependent Chromatin Remodeling

Song, Su Jung ; Poliseno, Laura ; Song, Min Sup ; Ala, Ugo ; Webster, Kaitlyn ; Ng, Christopher ; Beringer, Gary ; Brikbak, Nicolai J ; Yuan, Xin ; Cantley, Lewis C ; Richardson, Andrea L ; Pandolfi, Pier Paolo

Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis in mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en augmentant la prolifération cellulaire et l'angiogenèse, le facteur inhibiteur de la migration des macrophages, MIF, favorise le développement d'un cancer de la vessie

Macrophage Migratory Inhibitory Factor (MIF) promotes bladder cancer progression via increasing proliferation and angiogenesis

Choudhary, Shilpa ; Hegde, Poornima ; Pruitt, James R. ; Sielecki, Thais M. ; Choudhary, Dharamainder ; Scarpato, Kristen ; DeGraff, David J ; Pilbeam, Carol C ; Taylor, John A

Macrophage migratory inhibitory factor (MIF) is a proinflammatory cytokine shown to promote tumorigenesis. Using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model of bladder cancer, we previously showed that MIF knockout mice display decreased angiogenesis and invasion compared to wild-type. This study examines the role of MIF in bladder cancer via use of oral inhibitors of MIF. In vitro, high grade bladder cancer cells were treated with rhMIF+/- inhibitor. Measurements included cell [...]

Cet article passe en revue une décennie d'études sur le génome des cancers à partir de la publication de la séquence du génome humain

From human genome to cancer genome: The first decade

Wheeler, David A. ; Wang, Linghua

The realization that cancer progression required the participation of cellular genes provided one of several key rationales, in 1986, for embarking on the human genome project. Only with a reference genome sequence could the full spectrum of somatic changes leading to cancer be understood. Since its completion in 2003, the human reference genome sequence has fulfilled its promise as a foundational tool to illuminate the pathogenesis of cancer. Herein, we review the key historical milestones in [...]

Cet article passe en revue les travaux récents sur les mécanismes d'action des polymorphismes à simple nucléotide, pour la plupart localisés en dehors de régions codantes, identifiés dans des études d'association sur le génome entier

Lessons from Functional Analysis of Genome-Wide Association Studies

Sur, Inderpreet ; Tuupanen, Sari ; Whitington, Thomas ; Aaltonen, Lauri A. ; Taipale, Jussi

Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a [...]

Cet article passe en revue les travaux récents ayant mis en évidence des relations complexes entre quatre gènes impliqués dans le développement d'un carcinome à cellules rénales

Cooperation and Antagonism among Cancer Genes: The Renal Cancer Paradigm

Peña-Llopis, Samuel ; Christie, Alana ; Xie, Xian-Jin ; Brugarolas, James

It is poorly understood how driver mutations in cancer genes work together to promote tumor development. Renal cell carcinoma (RCC) offers a unique opportunity to study complex relationships among cancer genes. The four most commonly mutated genes in RCC of clear-cell type (the most common type) are two-hit tumor suppressor genes, and they cluster in a 43-Mb region on chromosome 3p that is deleted in approximately 90% of tumors: VHL (mutated in ∼80%), PBRM1 (∼50%), BAP1 (∼15%), and SETD2 [...]