A partir de données portant sur l'exome entier de 6 747 tumeurs (20 types de cancer), cette étude identifie des insertions/délétions dans les séquences microsatellites de gènes impliqués dans la cancérogenèse

Analysis of somatic microsatellite indels identifies driver events in human tumors

Maruvka, Yosef E. ; Mouw, Kent W. ; Karlic, Rosa ; Parasuraman, Prasanna ; Kamburov, Atanas ; Polak, Paz ; Haradhvala, Nicholas J. ; Hess, Julian M. ; Rheinbay, Esther ; Brody, Yehuda ; Koren, Amnon ; Braunstein, Lior Z. ; D'Andrea, Alan ; Lawrence, Michael S. ; Bass, Adam ; Bernards, Andre ; Michor, Franziska ; Getz, Gad

Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS [...]

A partir d'échantillons tumoraux prélevés sur 88 patients atteints d'un mésothéliome péritonéal, puis sur une cohorte complémentaire de 205 patients atteints d'un mésothéliome pleural, cette étude identifie, pour un petit nombre de patients atteints d'un mésothéliome péritonéal ne contenant pas de fibres d'amiante, la présence de réarrangements ALK

Identification of ALK rearrangements in malignant peritoneal mesothelioma

Hung, Y. P. ; Dong, F. ; Watkins, J. C. ; et al.,

Importance  Malignant peritoneal mesothelioma is a rare, aggressive tumor arising from the peritoneal lining, induced by asbestos, therapeutic radiation, or germline mutations. Nevertheless, the molecular features remain largely unknown. Objective  To investigate anaplastic lymphoma kinase (ALK) rearrangements in a large series of peritoneal mesothelioma and characterize the mutational landscape of these tumors. Design, Setting, and Participants  We studied 88 consecutive patients (39 men, 49 [...]

A partir d'échantillons de tissu dysplasique et de tissu tumoral prélevés sur 45 patients atteints d'un carcinome épidermoïde de l'œsophage, puis de 21 échantillons de tissu dysplasique prélevés sur 13 patients sans carcinome, cette étude identifie la présence, dans les échantillons de tissu dysplasique, d'un ensemble d'anomalies génomiques fréquemment observées dans les carcinomes

Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing

Chen, Xi-Xi ; Zhong, Qian ; Liu, Yang ; Yan, Shu-Mei ; Chen, Zhang-Hua ; Jin, Shan-Zhao ; Xia, Tian-Liang ; Li, Ruo-Yan ; Zhou, Ai-Jun ; Su, Zhe ; Huang, Yu-Hua ; Huang, Qi-Tao ; Huang, Li-Yun ; Zhang, Xing ; Zhao, Yan-Na ; Yun, Jin-Ping ; Wu, Qiu-Liang ; Lin, Dong-Xin ; Bai, Fan ; Zeng, Mu-sheng

Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported [...]

Menée à l'aide d'une technique de séquençage du génome entier sur des échantillons tumoraux prélevés sur 640 patientes atteintes d'un cancer du sein, cette étude identifie 11 tumeurs présentant un déficit du système de réparation des mésappariements

Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Davies, Helen ; Morganella, Sandro ; Purdie, Colin A. ; Jang, Se Jin ; Borgen, Elin ; Russnes, Hege ; Glodzik, Dominik ; Zou, Xueqing ; Viari, Alain ; Richardson, Andrea L. ; Børresen-Dale, Anne-Lise ; Thompson, Alastair ; Eyfjord, Jorunn E. ; Kong, Gu ; Stratton, Michael R. ; Nik-Zainal, Serena

Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels les ribosomes favorisent la cancérogenèse

How Ribosomes Translate Cancer

Sulima, Sergey O. ; Hofman, Isabel J. F. ; De Keersmaecker, Kim ; Dinman, Jonathan D.

A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here, we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis—from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en se liant à des séquences spécifiques de l'ADN, la protéine p53 exerce une fonction de suppresseur de tumeurs

Diverse p53/DNA binding modes expand the repertoire of p53 response elements

Vyas, Pratik ; Beno, Itai ; Xi, Zhiqun ; Stein, Yan ; Golovenko, Dmitrij ; Kessler, Naama ; Rotter, Varda ; Shakked, Zippora ; Haran, Tali E.

The tumor suppressor protein p53 acts as a transcription factor, binding sequence-specifically to defined DNA sites, thereby activating the expression of genes leading to diverse cellular outcomes. Canonical p53 response elements (REs) are made of two decameric half-sites separated by a variable number of base pairs (spacers). Fifty percent of all validated p53 REs contain spacers between 1 and 18 bp; however, their functional significance is unclear at present. Here, we show that p53 forms two [...]

Menée in vitro et in vivo sur des modèles de leucémie myéloïde, cette étude met en évidence le rôle joué par l'enzyme METTL3 dans la prolifération des cellules cancéreuses

The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells

Vu, Ly P. ; Pickering, Brian F. ; Cheng, Yuanming ; Zaccara, Sara ; Nguyen, Diu ; Minuesa, Gerard ; Chou, Timothy ; Chow, Arthur ; Saletore, Yogesh ; MacKay, Matthew ; Schulman, Jessica ; Famulare, Christopher ; Patel, Minal ; Klimek, Virginia M. ; Garrett-Bakelman, Francine E. ; Melnick, Ari ; Carroll, Martin ; Mason, Christopher E. ; Jaffrey, Samie R. ; Kharas, Michael G.

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, [...]

A partir d'échantillons de tissu sain et de tissu tumoral prélevés sur 10 patients atteints d'un carcinome rénal à cellules claires, puis menée sur 9 lignées cellulaires, cette étude met en évidence des mécanismes par lesquels la perte d'expression du gène VHL favorise l'activation de divers oncogènes

VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma

Yao, Xiaosai ; Tan, Jing ; Lim, Kevin Junliang ; Koh, Joanna ; Ooi, Wen Fong ; Li, Zhimei ; Huang, DaChuan ; Xing, Manjie ; Chan, Yang Sun ; Qu, James Zhengzhong ; Tay, Su Ting ; Wijaya, Giovani ; Lam, Yue Ning ; Hong, Jing Han ; Lee-Lim, Ai Ping ; Guan, Peiyong ; Ng, Michelle Shu Wen ; He, Cassandra Zhengxuan ; Suling Lin, Joyce ; Nandi, Tannistha ; Qamra, Aditi ; Xu, Chang ; Myint, Swe Swe ; Davies, James O. J. ; Goh, Jian Yuan ; Loh, Gary ; Tan, Bryan C. ; Rozen, Steven G. ; Yu, Qiang ; Huat Tan, Iain Bee ; Cheng, Christopher Wai Sam ; Li, Shang ; Chang, Kenneth Tou En ; Tan, Puay Hoon ; Silver, David Lawrence ; Lezhava, Alexander ; Steger, Gertrud ; Hughes, Jim R. ; Teh, Bin Tean ; Tan, Patrick

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel Lindau (VHL) tumor suppressor. Roles for non-coding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels, en stimulant l'autophagie et l'immunosuppression, un milieu acide favorise la progression d'une tumeur

Tumour acidosis: from the passenger to the driver's seat

Corbet, Cyril ; Feron, Olivier

The high metabolic demand of cancer cells leads to an accumulation of H+ ions in the tumour microenvironment. The disorganized tumour vasculature prevents an efficient wash-out of H+ ions released into the extracellular medium but also favours the development of tumour hypoxic regions associated with a shift towards glycolytic metabolism. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the production of lactate and a stoichiometric amount of H+ ions. [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels des cellules périvasculaires exprimant le gène Klf4 favorisent la formation de niches pré-métastatiques

KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis

Murgai, Meera ; Ju, Wei ; Eason, Matthew ; Kline, Jessica ; Beury, Daniel W. ; Kaczanowska, Sabina ; Miettinen, Markku M. ; Kruhlak, Michael ; Lei, Haiyan ; Shern, Jack F. ; Cherepanova, Olga A. ; Owens, Gary K. ; Kaplan, Rosandra N.

A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and [...]

A partir d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer de l'épithélium ovarien, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels des monocytes exprimant les récepteurs à angiopoïétine Tie2 favorisent l'angiogenèse et le processus métastatique

Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer

Wang, Xinjing ; Zhu, Qinyi ; Lin, Yingying ; Wu, Li ; Wu, Xiaoli ; Wang, Kai ; He, Qizhi ; Xu, Congjian ; Wan, Xiaoping ; Wang, Xipeng

Background: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14+Tie2+, TEMs) as key contributors to angiogenesis and metastasis of EOC. Methods: Tissue slides were evaluated by [...]

Menée sur des lignées cellulaires de cancer de la prostate résistant à la castration et à l'aide de xénogreffes, cette étude met en évidence des mécanismes de nature épigénétique par lesquels la protéine LSD1, qui régule l'activité transcriptionnelle du récepteur des androgènes, favorise l'expression du gène CENPE et la croissance tumorale

LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression

Liang, Yi ; Ahmed, Musaddeque ; Guo, Haiyang ; Soares, Fraser ; Hua, Junjie T. ; Gao, Shuai ; Lu, Catherine ; Poon, Christine ; Han, Wanting ; Langstein, Jens ; Ekram, Muhammad B. ; Li, Brian ; Davicioni, Elai ; Takhar, Mandeep ; Erho, Nicholas ; Karnes, R. Jeffrey ; Chadwick, Dianne ; van der Kwast, Theodorus ; Boutros, Paul C. ; Arrowsmith, Cheryl H. ; Feng, Felix Y. ; Joshua, Anthony Michael ; Zoubeidi, Amina ; Cai, Changmeng ; He, Housheng H.

Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa), and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant PCa (CRPC). Here we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell cycle [...]

Menée in vitro et in vivo sur des modèles de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, en ciblant la kinase TAK1, la protéine SAFB régule la voie de signalisation NF-kappaB et la progression tumorale

Down-regulation of SAFB sustains the NF-kappaB pathway by targeting TAK1 during the progression of colorectal cancer

Jiao, Hong-Li ; Ye, Ya-Ping ; Yang, Run-Wei ; Sun, Hui-Ying ; Wang, Shu-Yang ; Wang, Yong-Xia ; Xiao, Zhi-Yuan ; He, Liu-Qing ; Cai, Juan-Juan ; Wei, Wen-ting ; Chen, Yan-Ru ; Gu, Chun-cai ; Cai, Yue-Long ; Hu, Yun-Teng ; Lai, Qiu-Hua ; Qiu, Jun-Feng ; Liang, Li ; Cao, Guangwen ; Liao, Wen-Ting ; Ding, Yanqing

Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC). Experimental Design:SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffin-embedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay and chromatin immunoprecipitation (ChIP) were used to detect the [...]

Menée in vitro et in vivo sur des modèles de cancer du sein "basal-like", cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de Snail1, l'enzyme A20 favorise la transition épithélio-mésenchymateuse et le processus métastatique

A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1

Lee, Ji-Hyung ; Jung, Su Myung ; Yang, Kyung-Min ; Bae, Eunjin ; Ahn, Sung Gwe ; Park, Jin Seok ; Seo, Dongyeob ; Kim, Minbeom ; Ha, Jihoon ; Lee, Jaewon ; Kim, Jun-Hyeong ; Kim, Jun Hwan ; Ooshima, Akira ; Park, Jinah ; Shin, Donghyuk ; Lee, Youn Sook ; Lee, Sangho ; van Loo, Geert ; Jeong, Joon ; Kim, Seong-Jin ; Park, Seok Hee

Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-[beta]1-induced epithelial-mesenchymal [...]

Menée in vitro et in vivo sur des modèles de carcinome épidermoïde de la tête et du cou, cette étude met en évidence des mécanismes par lesquels, en limitant l'apoptose, un canal calcique (TMEM16A ) favorise la progression d'une tumeur

TMEM16A/ANO1 inhibits apoptosis via down-regulation of Bim expression

Godse, Neal R. ; Khan, Nayel I. ; Yochum, Zachary A. ; Gomez-Casal, Roberto ; Kemp, Carolyn ; Shiwarski, Daniel J. ; Seethala, Raja ; Kulich, Scott ; Seshadri, Mukund ; Burns, Timothy F. ; Duvvuri, Umamaheswar

Purpose: TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCC), raising the possibility of an anti-apoptotic role in malignant cells. The present study investigated this using a multi-modal, translational investigation. Experimental Design: Combination of 1) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression 2) in vivo studies assessing [...]

Menée à l'aide de la technologie CRISPR/Cas9 pour supprimer des gènes de réparation de l'ADN dans des organoïdes de cellules souches du côlon, cette étude met notamment en évidence des mécanismes par lesquels des erreurs de réplication de l'ADN induisent des mutations du gène de réparation des mésappariements MLH1

Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer

Drost, Jarno ; van Boxtel, Ruben ; Blokzijl, Francis ; Mizutani, Tomohiro ; Sasaki, Nobuo ; Sasselli, Valentina ; de Ligt, Joep ; Behjati, Sam ; Grolleman, Judith E. ; van Wezel, Tom ; Nik-Zainal, Serena ; Kuiper, Roland P. ; Cuppen, Edwin ; Clevers, Hans

Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology, and hold diagnostic and prognostic value. Here, we develop a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR/Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed sub-cloning and whole-genome sequencing. We found that mutation accumulation in organoids [...]

Cet article propose un cadre d'analyse, basé sur 4 composantes, pour mesurer l'évolution d'une tumeur en réponse à un traitement

Classifying the evolutionary and ecological features of neoplasms

Maley, Carlo C. ; Aktipis, Athena ; Graham, Trevor A. ; Sottoriva, Andrea ; Boddy, Amy M. ; Janiszewska, Michalina ; Silva, Ariosto S. ; Gerlinger, Marco ; Yuan, Yinyin ; Pienta, Kenneth J. ; Anderson, Karen S. ; Gatenby, Robert ; Swanton, Charles ; Posada, David ; Wu, Chung- I. ; Schiffman, Joshua D. ; Hwang, E. Shelley ; Polyak, Kornelia ; Anderson, Alexander R. A. ; Brown, Joel S. ; Greaves, Mel ; Shibata, Darryl

Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus [...]