A partir de 69 échantillons tumoraux prélevés sur 11 patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence une importante hétérogénéité génomique et épigénomique à l'intérieur de chaque tumeur

Genomic and epigenomic heterogeneity of hepatocellular carcinoma

Lin, De-Chen ; Mayakonda, Anand ; Dinh, Huy Q. ; Huang, Pinbo ; Lin, Lehang ; Liu, Xiaoping ; Ding, Ling-Wen ; Wang, Jie ; Berman, Benjamin ; Song, Erwei ; Yin, Dong ; Koeffler, H. Phillip

Understanding the intratumoral heterogeneity of hepatocellular carcinoma (HCC) is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 HCC cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 [...]

A partir de données issues des projets "1000 Genomes" et "The Cancer Genome Atlas", cette étude met en évidence la présence d'erreurs dans l'identification de variants rares

DNA damage is a pervasive cause of sequencing errors, directly confounding variant identification

Chen, Lixin ; Liu, Pingfang ; Evans, Thomas C. ; Ettwiller, Laurence M.

Large-scale sequencing studies have set out to determine the low-frequency pathogenic genetic variants in individuals and populations. However, Chen et al. demonstrate that many so-called low-frequency genetic variants in large public databases may be due to DNA damage. They scored libraries sequenced with and without a DNA damage–repairing enzymatic mix to assess the proportion of true rare variants. It remains to be seen how best to repair DNA before sequencing to provide more accurate [...]

A partir d'échantillons tumoraux prélevés sur 102 patients atteints d'une tumeur neuroendocrine du pancréas, cette étude identifie un ensemble de mutations constitutionnelles et somatiques

Whole-genome landscape of pancreatic neuroendocrine tumours

Scarpa, Aldo ; Chang, David K. ; Nones, Katia ; Corbo, Vincenzo ; Patch, Ann-Marie ; Bailey, Peter ; Lawlor, Rita T. ; Johns, Amber L. ; Miller, David K. ; Mafficini, Andrea ; Rusev, Borislav ; Scardoni, Maria ; Antonello, Davide ; Barbi, Stefano ; Sikora, Katarzyna O. ; Cingarlini, Sara ; Vicentini, Caterina ; McKay, Skye ; Quinn, Michael C. J. ; Bruxner, Timothy J. C. ; Christ, Angelika N. ; Harliwong, Ivon ; Idrisoglu, Senel ; McLean, Suzanne ; Nourse, Craig ; Nourbakhsh, Ehsan ; Wilson, Peter J. ; Anderson, Matthew J. ; Fink, J. Lynn ; Newell, Felicity ; Waddell, Nick ; Holmes, Oliver ; Kazakoff, Stephen H. ; Leonard, Conrad ; Wood, Scott ; Xu, Qinying ; Nagaraj, Shivashankar Hiriyur ; Amato, Eliana ; Dalai, Irene ; Bersani, Samantha ; Cataldo, Ivana ; Dei Tos, Angelo P. ; Capelli, Paola ; Davì, Maria Vittoria ; Landoni, Luca ; Malpaga, Anna ; Miotto, Marco ; Whitehall, Vicki L. J. ; Leggett, Barbara A. ; Harris, Janelle L. ; Harris, Jonathan ; Jones, Marc D. ; Humphris, Jeremy ; Chantrill, Lorraine A. ; Chin, Venessa ; Nagrial, Adnan M. ; Pajic, Marina ; Scarlett, Christopher J. ; Pinho, Andreia ; Rooman, Ilse ; Toon, Christopher ; Wu, Jianmin ; Pinese, Mark ; Cowley, Mark ; Barbour, Andrew ; Mawson, Amanda ; Humphrey, Emily S. ; Colvin, Emily K. ; Chou, Angela ; Lovell, Jessica A. ; Jamieson, Nigel B. ; Duthie, Fraser ; Gingras, Marie-Claude ; Fisher, William E. ; Dagg, Rebecca A. ; Lau, Loretta M. S. ; Lee, Michael ; Pickett, Hilda A. ; Reddel, Roger R. ; Samra, Jaswinder S. ; Kench, James G. ; Merrett, Neil D. ; Epari, Krishna ; Nguyen, Nam Q. ; Zeps, Nikolajs ; Falconi, Massimo ; Simbolo, Michele ; Butturini, Giovanni ; Van Buren, George ; Partelli, Stefano ; Fassan, Matteo ; Australian Pancreatic Cancer Genome, Initiative ; Khanna, Kum Kum ; Gill, Anthony J. ; Wheeler, David A. ; Gibbs, Richard A. ; Musgrove, Elizabeth A. ; Bassi, Claudio ; Tortora, Giampaolo ; Pederzoli, Paolo ; Pearson, John V. ; Waddell, Nicola ; Biankin, Andrew V. ; Grimmond, Sean M.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. [...]

Menée in vitro, in vivo et à l'aide de données issues du projet "The Cancer Genome Atlas", cette étude identifie des mécanismes par lesquels, en présence d'un gène KRAS muté, une surexpression du facteur de transcription FOSL1 favorise le développement d'un adénocarcinome canalaire du pancréas ou d'un adénocarcinome du poumon

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

Vallejo, Adrian ; Perurena, Naiara ; Guruceaga, Elisabet ; Mazur, Pawel K. ; Martinez-Canarias, Susana ; Zandueta, Carolina ; Valencia, Karmele ; Arricibita, Andrea ; Gwinn, Dana ; Sayles, Leanne C. ; Chuang, Chen-Hua ; Guembe, Laura ; Bailey, Peter ; Chang, David K. ; Biankin, Andrew ; Ponz-Sarvise, Mariano ; Andersen, Jesper B. ; Khatri, Purvesh ; Bozec, Aline ; Sweet-Cordero, E. Alejandro ; Sage, Julien ; Lecanda, Fernando ; Vicent, Silve

KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and [...]

Menée à l'aide de modèles murins transgéniques de leucémie aiguë lymphoblastique pré B, cette étude met en évidence des mécanismes de nature métabolique par lesquels, en limitant les niveaux cellulaires d'adénosine triphosphate, des facteurs de transcription de la lignée lymphoïde B inhibent la transformation maligne

Metabolic gatekeeper function of B-lymphoid transcription factors

Chan, Lai N. ; Chen, Zhengshan ; Braas, Daniel ; Lee, Jae-Woong ; Xiao, Gang ; Geng, Huimin ; Cosgun, Kadriye Nehir ; Hurtz, Christian ; Shojaee, Seyedmehdi ; Cazzaniga, Valeria ; Schjerven, Hilde ; Ernst, Thomas ; Hochhaus, Andreas ; Kornblau, Steven M. ; Konopleva, Marina ; Pufall, Miles A. ; Cazzaniga, Giovanni ; Liu, Grace J. ; Milne, Thomas A. ; Koeffler, H. Phillip ; Ross, Theodora S. ; Sanchez-Garcia, Isidro ; Borkhardt, Arndt ; Yamamoto, Keith R. ; Dickins, Ross A. ; Graeber, Thomas G. ; Müschen, Markus

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and [...]

Menée in vitro sur un modèle de cancer du poumon non à petites cellules, cette étude identifie un ensemble de gènes (suppresseurs de tumeurs et oncogènes) impliqués dans la régulation de la prolifération et de la survie des cellules cancéreuses en cas d'anomalies de la signalisation EGFR

A genetic interaction analysis identifies cancer drivers that modify EGFR dependency

Liao, Sida ; Davoli, Teresa ; Leng, Yumei ; Li, Mamie Z. ; Xu, Qikai ; Elledge, Stephen J.

A large number of cancer drivers have been identified through tumor sequencing efforts, but how they interact and the degree to which they can substitute for each other have not been systematically explored. To comprehensively investigate how cancer drivers genetically interact, we searched for modifiers of epidermal growth factor receptor (EGFR) dependency by performing CRISPR, shRNA, and expression screens in a non-small cell lung cancer (NSCLC) model. We elucidated a broad spectrum of tumor [...]

Menée à l'aide de deux modèles murins d'adénocarcinome du poumon présentant la mutation G12D du gène KRAS, cette étude met en évidence des mécanismes par lesquels une histone méthyltransférase, Setd2, exerce une fonction de suppresseur de tumeurs

Systematic in vivo inactivation of chromatin regulating enzymes identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma

Walter, David M. ; Venancio, Olivia S. ; Buza, Elizabeth L. ; Tobias, John W. ; Deshpande, Charuhas ; Gudiel, A. Andrea ; Kim-Kiselak, Caroline ; Cicchini, Michelle ; Yates, Travis J. ; Feldser, David M.

Chromatin modifying genes are frequently mutated in human lung adenocarcinoma, but the functional impact of these mutations on disease initiation and progression is not well understood. Using a CRISPR-based approach, we systematically inactivated three of the most commonly mutated chromatin regulatory genes in two KrasG12D-driven mouse models of lung adenocarcinoma to characterize the impact of their loss. Targeted inactivation of SWI/SNF nucleosome remodeling complex members Smarca4 (Brg1) or [...]

Menée à l'aide d'échantillons tumoraux et sanguins prélevés sur des patients atteints d'un cancer colorectal, puis menée in vitro, cette étude met en évidence le rôle joué par la pyruvate déshydrogénase kinase PDK4 dans la transformation maligne

Oncogenic role of PDK4 in human colon cancer cells

Leclerc, D. ; Pham, D. N. T. ; Levesque, N. ; Truongcao, M. ; Foulkes, W. D. ; Sapienza, C. ; Rozen, R.

Background: Cancer cells maintain high rates of glycolysis. Pyruvate dehydrogenase kinases (PDK) contribute to this phenomenon, which favours apoptosis resistance and cellular transformation. We previously reported upregulation of PDK4 in normal mucosa of colorectal cancer (CRC) patients compared with controls and in preneoplastic intestine of our mouse model. Decreased methylation of four consecutive PDK4 CpGs was observed in normal mucosa of patients. Although other members of the PDK family [...]

A partir d'échantillons tumoraux prélevés sur 608 patientes atteintes d'un cancer du sein, puis menée in vitro et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels une surexpression du gène EVI1 favorise le développement d'une tumeur ER- ou HER2-

Prominent oncogenic roles of EVI1 in breast carcinoma

Wang, Hui ; Schaefer, Thorsten ; Konantz, Martina ; Braun, Martin ; Varga, Zsuzsanna ; Paczulla, Anna M. ; Reich, Selina ; Jacob, Francis ; Perner, Sven ; Moch, Holger ; Fehm, Tanja ; Kanz, Lothar ; Schulze-Osthoff, Klaus ; Lengerke, Claudia

Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma (BC) where its contributions are unexplored. Analyzing a tissue microarray of 608 BC patient specimens, we documented EVI1 overexpression in both estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) BC. Here we report prognostic relevance of EVI1 overexpression in triple-negative BC (TNBC) but not in the HER2-positive BC subset. In human [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en exerçant une pression physique sur les cellules cancéreuses, les fibroblastes associés au cancer favorisent le processus invasif

A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion

Labernadie, Anna ; Kato, Takuya ; Brugues, Agusti ; Serra-Picamal, Xavier ; Derzsi, Stefanie ; Arwert, Esther ; Weston, Anne ; Gonzalez-Tarrago, Victor ; Elosegui-Artola, Alberto ; Albertazzi, Lorenzo ; Alcaraz, Jordi ; Roca-Cusachs, Pere ; Sahai, Erik ; Trepat, Xavier

Cancer-associated fibroblasts (CAFs) promote tumour invasion and metastasis. We show that CAFs exert a physical force on cancer cells that enables their collective invasion. Force transmission is mediated by a heterophilic adhesion involving N-cadherin at the CAF membrane and E-cadherin at the cancer cell membrane. This adhesion is mechanically active; when subjected to force it triggers [beta]-catenin recruitment and adhesion reinforcement dependent on [alpha]-catenin/vinculin interaction. [...]

Menée à l'aide d'un modèle murin d'adénocarcinome du poumon, cette étude identifie une voie de signalisation impliquant la protéine CD109, les kinases JAK et le facteur de transcription Stat3 pour favoriser le processus métastatique

Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis

Chuang, Chen-Hua ; Greenside, Peyton G. ; Rogers, Zoe N. ; Brady, Jennifer J. ; Yang, Dian ; Ma, Rosanna K. ; Caswell, Deborah R. ; Chiou, Shin-Heng ; Winters, Aidan F. ; Gruner, Barbara M. ; Ramaswami, Gokul ; Spencley, Andrew L. ; Kopecky, Kimberly E. ; Sayles, Leanne C. ; Sweet-Cordero, E. Alejandro ; Li, Jin Billy ; Kundaje, Anshul ; Winslow, Monte M.

Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers [...]

Menée in vitro et in vivo sur des modèles d'adénocarcinome du poumon, cette étude met en évidence des mécanismes par lesquels la surexpression d'un récepteur de l'acide hyaluronique (HMMR) dans la matrice extracelluaire favorise la formation de métastases cérébrales

Extracellular matrix receptor expression in subtypes of lung adenocarcinoma potentiates outgrowth of micrometastases

Stevens, Laura E. ; Cheung, William K. C. ; Adua, Sally J. ; Arnal-Estapé, Anna ; Zhao, Minghui ; Liu, Zongzhi ; Brewer, Kelly ; Herbst, Roy S. ; Nguyen, Don X.

Mechanisms underlying the propensity of latent lung adenocarcinoma (LUAD) to relapse are poorly understood. In this study, we show how differential expression of a network of extracellular matrix (ECM) molecules and their interacting proteins contributes to risk of relapse in distinct LUAD subtypes. Overexpression of the hyaluronan receptor HMMR in primary LUAD was associated with an inflammatory molecular signature and poor prognosis. Attenuating HMMR in LUAD cells diminished their ability to [...]

Menée à l'aide de modèles murins de cancer colorectal, cette étude met en évidence des mécanismes par lesquels une surexpression de la protéine Six1 favorise la croissance tumorale et le processus métastatique

Six1 promotes colorectal cancer growth and metastasis by stimulating angiogenesis and recruiting tumor-associated macrophages

Hanwen Xu ; Yu Zhang ; Maria M. Peña ; Lucia Pirisi ; Kim E. Creek

The homeoprotein Six1 is overexpressed in many human cancers and is associated with increased tumor progression and metastasis. Recent studies have shown that Six1 is associated with poorer overall survival in advanced-stage colorectal cancer (CRC). In the current study, we explored the functional changes and molecular events associated with Six1 overexpression in a mouse model of CRC. An orthotopic model and a splenic injection metastasis model were used to investigate the role of Six1 in CRC [...]

Menée à l'aide de xénogreffes de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, indépendamment de la présence de mutations du gène KRAS, la signalisation MAPK dans différents types cellulaires régule la transition épithélio-mésenchymateuse, la prolifération des cellules souches cancéreuses et la croissance tumorale

Oncogenic effects of high MAPK activity in colorectal cancer mark progenitor cells and persist irrespective of RAS mutations

Blaj, Cristina ; Schmidt, Eva Marina ; Lamprecht, Sebastian ; Hermeking, Heiko ; Jung, Andreas ; Kirchner, Thomas ; Horst, David

About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling which promotes tumor invasion and progression. Here we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status. Using primary colorectal cancer tissues, xenograft models and MAPK reporter constructs, we showed that tumor cells with high MAPK activity resided specifically at the [...]

Menée à l'aide de modèles murins de cancer du sein, cette étude met en évidence le rôle joué par les mégacaryocytes pour prévenir le développement de métastases osseuses

The Role of Megakaryocytes in Breast Cancer Metastasis to Bone

Jackson, Walter ; Sosnoski, Donna M. ; Ohanessian, Sara E. ; Chandler, Paige ; Mobley, Adam w ; Meisel, Kacey D. ; Mastro, Andrea M.

Little is known about how megakaryocytes affect metastasis apart from serving as the source of platelets. We noted an increase in the number of megakaryocytes in the femurs of metastases-bearing athymic mice four weeks following intracardiac inoculation of MDA-MB-231 human breast cancer cells. How did the megakaryocytes relate to the metastases? Did megakaryocytes prepare a niche or did they increase in response to metastases? To test these possibilities, we examined two models of experimental [...]

Cet article passe en revue les travaux récents sur l'intérêt des modèles murins génétiquement modifiés pour l'étude des leucémies et des lymphomes

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

Goldberg, Liat ; Gough, Sheryl M. ; Lee, Fan ; Dang, Christine ; Walker, Robert L. ; Zhu, Yeulin J. ; Bilke, Sven ; Pineda, Marbin ; Onozawa, Masahiro ; Chung, Yang Jo ; Meltzer, Paul S. ; Aplan, Peter D.

Malignant transformation is a multistep process that is dictated by acquisition of multiple genomic aberrations that provide growth and survival advantage. During the post genomic era, high throughput genomic sequencing has advanced exponentially, leading to identification of countless cancer associated mutations with potential for targeted therapy. Mouse models of cancer serve as excellent tools to examine the functionality of gene mutations and their contribution to the malignant process. [...]

Cet article passe en revue les outils et les méthodes permettant de dresser un arbre phylogénétique de l'évolution d'une tumeur

The evolution of tumour phylogenetics: principles and practice

Schwartz, Russell ; Schaffer, Alejandro A.

Rapid advances in high-throughput sequencing and a growing realization of the importance of evolutionary theory to cancer genomics have led to a proliferation of phylogenetic studies of tumour progression. These studies have yielded not only new insights but also a plethora of experimental approaches, sometimes reaching conflicting or poorly supported conclusions. Here, we consider this body of work in light of the key computational principles underpinning phylogenetic inference, with the goal [...]