Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un chordome (24 cas issus de 8 familles affectées par la maladie, 103 cas sporadiques), cette étude identifie des variants du gène T associés à un risque de chordome familial ou sporadique

Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma

Kelley, MichaelJ ; Shi, Jianxin ; Ballew, Bari ; Hyland, PaulaL ; Li, Wen-Qing ; Rotunno, Melissa ; Alcorta, DavidA ; Liebsch, NorbertJ ; Mitchell, Jason ; Bass, Sara ; Roberson, David ; Boland, Joseph ; Cullen, Michael ; He, Ji ; Burdette, Laurie ; Yeager, Meredith ; Chanock, StephenJ ; Parry, DilysM ; Goldstein, AlisaM ; Yang, XiaohongR

Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated [...]

Menée sur 230 échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome du poumon, cette étude du projet "The Cancer Genome Atlas" identifie notamment des mutations somatiques fréquentes dans 18 gènes

Comprehensive molecular profiling of lung adenocarcinoma

The Cancer Genome Atlas Research, Network

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually [...]

Menée sur des cellules souches cancéreuses et des échantillons de tumeurs primitives prélevés sur 12 patientes atteintes d'un cancer du sein, cette étude de séquençage de l'exome analyse et compare les mutations somatiques observées dans les cellules souches cancéreuses et les cellules tumorales

Sequencing of breast cancer stem cell populations indicates a dynamic conversion between differentiation states in vivo

Klevebring, Daniel ; Rosin, Gustaf ; Ma, Ran ; Lindberg, Johan ; Czene, Kamila ; Kere, Juha ; Fredriksson, Irma ; Bergh, Jonas ; Hartman, Johan

INTRODUCTION:The cancer stem cell model implies a hierarchical organization within breast tumors maintained by cancer stem-like cells (CSCs). Accordingly, CSCs are a subpopulation of cancer cells with capacity for self-renewal, differentiation and tumor initiation. These cells can be isolated through the phenotypic markers CD44+/CD24-, expression of ALDH1 and an ability to form nonadherent, multicellular spheres in vitro. However, controversies to describe the stem cell model exist; it is [...]

Menée sur 57 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un carcinome de la vésicule biliaire, cette étude identifie des mutations fréquentes de plusieurs gènes impliqués dans la signalisation ErbB

Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway

Li, Maolan ; Zhang, Zhou ; Li, Xiaoguang ; Ye, Junyi ; Wu, Xiangsong ; Tan, Zhujun ; Liu, Chang ; Shen, Baiyong ; Wang, Xu-An ; Wu, Wenguang ; Zhou, Daizhan ; Zhang, Di ; Wang, Ting ; Liu, Bingya ; Qu, Kai ; Ding, Qichen ; Weng, Hao ; Ding, Qian ; Mu, Jiasheng ; Shu, Yijun ; Bao, Runfa ; Cao, Yang ; Chen, Peizhan ; Liu, Tianyu ; Jiang, Lin ; Hu, Yunping ; Dong, Ping ; Gu, Jun ; Lu, Wei ; Shi, Weibin ; Lu, Jianhua ; Gong, Wei ; Tang, Zhaohui ; Zhang, Yong ; Wang, Xuefeng ; Chin, Y. Eugene ; Weng, Xiaoling ; Zhang, Hong ; Tang, Wei ; Zheng, Yonglan ; He, Lin ; Wang, Hui ; Liu, Yun ; Liu, Yingbin

Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR) < 0.05) of non-silent mutations include TP53 [...]

Menée sur des échantillons tumoraux prélevés sur 84 patients atteints d'un améloblastome et 40 patients atteints d'un autre type de tumeur odontogénique, cette étude identifie de fréquentes mutations somatiques activant les gènes FGRFR2, RAS et BRAF, ainsi que des mutations secondaires dans d'autres gènes (SMO, CTNNB1, PIK3CA et SMARCB1)

Activating FGFR2-RAS-BRAF Mutations in Ameloblastoma

Brown, Noah A. ; Rolland, Delphine CM ; McHugh, Jonathan B. ; Weigelin, Helmut C. ; Zhao, Lili L. ; Lim, Megan S. ; Elenitoba-Johnson, Kojo SJ ; Betz, Bryan L.

Purpose: Ameloblastoma is an odontogenic neoplasm whose overall mutational landscape has not been well characterized. We sought to characterize pathogenic mutations in ameloblastoma and their clinical and functional significance with an emphasis on the mitogen-activated protein kinase (MAPK) pathway. Experimental Design: A total of 84 ameloblastomas and 40 non-ameloblastoma odontogenic tumors were evaluated with a combination of BRAF V600E allele-specific PCR, VE1 immunohistochemistry, the Ion [...]

Menée sur des lignées cellulaires et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, dans les cellules tumorales, l'oncoprotéine MYC active et réprime l'expression d'un groupe de gènes

Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles

Walz, Susanne ; Lorenzin, Francesca ; Morton, Jennifer ; Wiese, Katrin E. ; von Eyss, Bjorn ; Herold, Steffi ; Rycak, Lukas ; Dumay-Odelot, Helene ; Karim, Saadia ; Bartkuhn, Marek ; Roels, Frederik ; Wustefeld, Torsten ; Fischer, Matthias ; Teichmann, Martin ; Zender, Lars ; Wei, Chia-Lin ; Sansom, Owen ; Wolf, Elmar ; Eilers, Martin

In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour [...]

Cet article passe en revue les travaux récents sur le réseau de gènes qui, en interaction avec le suppresseur de tumeurs PALB2, sont impliqués dans l'entretien de la stabilité génomique

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

Park, Jung-Young ; Zhang, Fan ; Andreassen, Paul R.

PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it [...]

Menée sur des lignées cellulaires et à l'aide de modèles murins de lymphome, cette étude met en évidence des mécanismes par lesquels la protéine Myc régule l'expression d'un groupe de gènes cibles

Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis

Sabo, Arianna ; Kress, Theresia R. ; Pelizzola, Mattia ; de Pretis, Stefano ; Gorski, Marcin M. ; Tesi, Alessandra ; Morelli, Marco J. ; Bora, Pranami ; Doni, Mirko ; Verrecchia, Alessandro ; Tonelli, Claudia ; Faga, Giovanni ; Bianchi, Valerio ; Ronchi, Alberto ; Low, Diana ; Muller, Heiko ; Guccione, Ernesto ; Campaner, Stefano ; Amati, Bruno

The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci. Recent work suggested that rather than up- and downregulating selected groups of genes, Myc targets all active promoters and enhancers in the genome (a phenomenon termed ‘invasion’) and acts as a general amplifier of transcription. However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide [...]

Menée à l'aide de modèles murins et d'échantillons prélevés sur 15 patients atteints d'un lymphome, cette étude met en évidence une signature basée sur l'expression de phospholipides en association avec une surexpression du gène MYC

Alteration of the lipid profile in lymphomas induced by MYC overexpression

Eberlin, Livia S. ; Gabay, Meital ; Fan, Alice C. ; Gouw, Arvin M. ; Tibshirani, Robert J. ; Felsher, Dean W. ; Zare, Richard N.

Overexpression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene is one of the most commonly implicated causes of human tumorigenesis. MYC is known to regulate many aspects of cellular biology including glucose and glutamine metabolism. Little is known about the relationship between MYC and the appearance and disappearance of specific lipid species. We use desorption electrospray ionization mass spectrometry imaging (DESI-MSI), statistical analysis, and conditional [...]

Menée sur des lignées cellulaires de mélanome, cette étude met en évidence des mécanismes de phosphorylation du gène suppresseur de tumeur PDCD4 par la protéine kinase RSK

Phosphoproteomic analysis identifies the tumor suppressor PDCD4 as a RSK substrate negatively regulated by 14-3-3

Galan, Jacob A. ; Geraghty, Kathryn M. ; Lavoie, Geneviève ; Kanshin, Evgeny ; Tcherkezian, Joseph ; Calabrese, Viviane ; Jeschke, Grace R. ; Turk, Benjamin E. ; Ballif, Bryan A. ; Blenis, John ; Thibault, Pierre ; Roux, Philippe P.

The Ras/MAPK signaling cascade regulates various biological functions, including cell growth and proliferation. As such, this pathway is frequently deregulated in several types of cancer, including most cases of melanoma. RSK (p90 ribosomal S6 kinase) is a MAPK-activated protein kinase required for melanoma growth and proliferation, but relatively little is known about its exact function and the nature of its substrates. Herein, we used a quantitative phosphoproteomics approach to define the [...]

Menée sur des lignées cellulaires et 36 échantillons tumoraux prélevés sur des patients atteints d'un carcinome du poumon non à petites cellules, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du gène KRT18, le facteur de transcription EGR1 exerce une fonction de suppresseur de tumeurs

EGR1 decreases the malignancy of human non-small cell lung carcinoma by regulating KRT18 expression

Zhang, Huihua ; Chen, Xiaojia ; Wang, Jiakang ; Guang, Wenhua ; Han, Wei ; Zhang, Hang ; Tan, Xuan ; Gu, Yong

Early growth response 1 (EGR1) is a multifunctional transcription factor; Positive and negative functions of EGR1 in various tumors rely on the integrated functions of various genes it regulates. In this study, we observed the role of EGR1 in non-small-cell lung carcinoma (NSCLC) and identified genes that influence cell fate and tumor development. Various assays showed that EGR1 arrested cell mobility, inhibited migration, and induced apoptosis. Microarray analysis revealed that 100 genes, [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels l'absence d'expression du gène p62 dans le micro-environnement tumoral ou les fibroblastes du stroma favorise la croissance tumorale

Metabolic Reprogramming of Stromal Fibroblasts through p62-mTORC1 Signaling Promotes Inflammation and Tumorigenesis

Valencia, Tania ; Kim, Ji Young ; Abu-Baker, Shadi ; Moscat-Pardos, Jorge ; Ahn, Christopher S ; Reina-Campos, Miguel ; Duran, Angeles ; Castilla, Elias A ; Metallo, Christian M ; Diaz-Meco, Maria T ; Moscat, Jorge

The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and [...]

Menée sur des lignées cellulaires de cancer du sein, cette étude met en évidence des mécanismes par lesquels, via une interaction avec des transcrits de deux gènes (APP et ZNF395), la protéine TARBP2 favorise le processus métastatique

Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins

Goodarzi, Hani ; Zhang, Steven ; Buss, Colin G. ; Fish, Lisa ; Tavazoie, Saeed ; Tavazoie, Sohail F.

Aberrant regulation of RNA stability has an important role in many disease states. Deregulated post-transcriptional modulation, such as that governed by microRNAs targeting linear sequence elements in messenger RNAs, has been implicated in the progression of many cancer types. A defining feature of RNA is its ability to fold into structures. However, the roles of structural mRNA elements in cancer progression remain unexplored. Here we performed an unbiased search for post-transcriptional [...]

Cet article passe en revue les travaux récents sur les logiciels d'analyse des génomes du cancer

Expanding the computational toolbox for mining cancer genomes

Ding, Li ; Wendl, Michael C. ; McMichael, Joshua F. ; Raphael, Benjamin J.

High-throughput DNA sequencing has revolutionized the study of cancer genomics with numerous discoveries that are relevant to cancer diagnosis and treatment. The latest sequencing and analysis methods have successfully identified somatic alterations, including single-nucleotide variants, insertions and deletions, copy-number aberrations, structural variants and gene fusions. Additional computational techniques have proved useful for defining the mutations, genes and molecular networks that [...]