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| Open AccessA genetic cell context-dependent role for ZEB1 in lung cancer
ZEB1 is a driver of epithelial-to-mesenchymal transition that usually promotes lung cancer in the context of KRAS mutation. Here, the authors uncover a growth suppressive role for ZEB1 in EGFRmutant lung adenocarcinoma, thus elucidating the context dependent function of this protein.
- Ting Zhang
- , Lixia Guo
- & Yanan Yang
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Article
| Open AccessGenome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma
Cutaneous squamous cell carcinoma is the second most common type of skin cancer. In this genome-wide association study, which includes over 7,000 cases, the authors identify 4 new susceptibility loci for this cancer and also provide independent replication of 9 previously reported susceptibility loci.
- Harvind S. Chahal
- , Yuan Lin
- & Kavita Y. Sarin
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Article
| Open AccessChallenges in identifying cancer genes by analysis of exome sequencing data
Next generation sequencing has been pivotal in identifying somatic mutations in cancer samples. In this study, the authors analyse whole exome sequencing data using a variety of bioinformatic methods to identify mutations in known cancer genes and find that many cancer genes are not detected by these methods.
- Matan Hofree
- , Hannah Carter
- & Trey Ideker
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Article
| Open AccessA whole-genome sequence and transcriptome perspective on HER2-positive breast cancers
Breast cancer is separated into multiple subtypes based on the expression of HER2 and hormone receptors. Here, the authors report the whole genome sequence of 64 HER2 positive tumours and show that these can be further separated into four groups with different gene expression profiles and genomic features.
- Anthony Ferrari
- , Anne Vincent-Salomon
- & Gilles Thomas
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Article
| Open AccessGermline MC1R status influences somatic mutation burden in melanoma
Deleterious germline variants in the MC1Rgene are associated with red hair and freckles, and with an increased risk of developing melanoma. Here, the authors investigate melanoma samples from patients with and without these variants and find that their presence is predictive of a higher overall mutation prevalence.
- Carla Daniela Robles-Espinoza
- , Nicola D. Roberts
- & David J. Adams
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Article
| Open AccessRUBIC identifies driver genes by detecting recurrent DNA copy number breaks
Analysis of cancer genome sequencing data has been used to predict genes associated with the pathogenesis of cancer. Here, the authors propose a new algorithm entitled RUBIC that predicts breaks in DNA as opposed to previously published methods that predict amplifications and deletions of DNA.
- Ewald van Dyk
- , Marlous Hoogstraat
- & Lodewyk F. A. Wessels
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Article
| Open AccessFunctional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41
A common susceptibility haplotype for renal cell carcinoma is located on chromosome 12p12.1. Here, the authors show that the variant rs7132434 alters binding of the AP-1 transcription factor, which increases the expression of BHLHE41in renal cells.
- Pierre Bigot
- , Leandro M. Colli
- & Stephen J. Chanock
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Article
| Open AccessPatients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes
Some individuals present with multiple synchronous colorectal tumours, but the genetic understanding of this is unclear. Here, the authors use a sequencing strategy to show that the synchronous tumours are genetically independent and the patients harbour rare germline damaging mutations in genes associated with the immune system.
- Matteo Cereda
- , Gennaro Gambardella
- & Francesca D. Ciccarelli
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Article
| Open AccessThe landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis
Genetically engineered mouse models of cancer are useful in identifying oncogenes and tumour suppressors. Here, the authors use gene expression profiles to generate a catalogue of copy number aberrations in 45 mouse models, and compare mouse and human tumours to identify additional drivers of tumorigenesis.
- Uri Ben-David
- , Gavin Ha
- & Todd R. Golub
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Article
| Open AccessGenome-wide association study identifies multiple susceptibility loci for multiple myeloma
Previous genome-wide association studies have identified loci associated with the risk of multiple myeloma. Here, the authors present a meta-analysis of six genome wide association studies of the disease and identify eight new loci; functional studies identify genes as candidates for the basis of these associations.
- Jonathan S. Mitchell
- , Ni Li
- & Richard S. Houlston
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Article
| Open AccessWhole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer
The genomic features of metastatic prostate cancer are beginning to be understood. Here, the authors performed whole genome sequencing of plasma samples from these patients and found a high plasticity of the cancer genomes with newly occurring focal amplifications as a driving force in progression.
- Peter Ulz
- , Jelena Belic
- & Michael R. Speicher
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Article
| Open AccessRare disruptive mutations and their contribution to the heritable risk of colorectal cancer
The genetic factors that predispose individuals to familial colorectal cancer are poorly understood. In this study, the authors use whole exome sequencing of 1,006 patients and 1,609 healthy controls and show it is unlikely that further major high-penetrance susceptibility genes exist.
- Daniel Chubb
- , Peter Broderick
- & Richard S. Houlston
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Article
| Open AccessOncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer
Cancer cells rely on glutamine to replenish the TCA cycle. Here, the authors show that oncogenic PIK3CAmutations drive this metabolic rewiring in colorectal cancer cells by up-regulating glutamate pyruvate transaminase expression, thus increasing sensitivity to glutamine starvation.
- Yujun Hao
- , Yardena Samuels
- & Zhenghe Wang
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Article
| Open AccessFemale chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk
- Mitchell J. Machiela
- , Weiyin Zhou
- & Stephen J. Chanock
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Article
| Open AccessSpatial niche formation but not malignant progression is a driving force for intratumoural heterogeneity
It has been increasingly recognised that tumours are not made up of a homogeneous population of cells. Here, the authors show heterogeneous expression of five protein markers in renal cell cancer and demonstrate that the progression of the tumour does not influence the degree of heterogeneity in the tumour.
- Rouven Hoefflin
- , Bernd Lahrmann
- & Stefan Duensing
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Article
| Open AccessIdentification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia
The fusion of two genes during the pathogenesis of cancer can create oncogenes. In this study, the authors screen pediatric B-cell precursor acute lymphoblastic leukaemia samples for the presence of fusion genes and describe fusion genes that define new molecular subtypes of the disease
- Henrik Lilljebjörn
- , Rasmus Henningsson
- & Thoas Fioretos
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Article
| Open AccessZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation
The t(8;21) translocation is often found in acute myeloid leukaemia but is not sufficient for development of the disease. In this study, the authors identify frequent mutations in the transcriptional repressor, ZBTB7A, in these patients and show that the mutations reduce DNA binding activity.
- Luise Hartmann
- , Sayantanee Dutta
- & Philipp A. Greif
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Article
| Open AccessClonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition
The BTK inhibitor ibrutinib is used to treat chronic lymphocytic leukaemia, however some patients develop resistance to the drug. Here, the authors use genomic analyses to examine the clonal evolution of 5 patients that develop resistance to ibrutinib.
- Jan A. Burger
- , Dan A. Landau
- & Catherine J. Wu
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Article
| Open AccessSuppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK
KRas is frequently mutated in multiple cancer types; identifying drugs to treat such cancers is a good therapeutic strategy. Here, the authors perform a synthetic lethal screen in mice and show that inhibiting Plk1 and ROCK results in the inhibition of tumour growth by increasing expression of the tumour suppressor p21.
- Jieqiong Wang
- , Kewen Hu
- & Mingyao Liu
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Article
| Open AccessHeterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant
Fulvestrant degrades the oestrogen receptor. Here, the authors report on a clinical trial using fulvestrant and show that mutations in the oestrogen receptor alpha gene are prevalent in circulating tumour DNA and do not influence the clinical outcome of patients to fulvestrant.
- Jill M. Spoerke
- , Steven Gendreau
- & Mark R. Lackner
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Article
| Open AccessPatient-specific factors influence somatic variation patterns in von Hippel–Lindau disease renal tumours
Analysing multiple tumours from the same patient permits the study of the germline contribution to cancer. Here, the authors sequence multiple renal tumours from VHL patients and find that intra-patient tumours are clonally distinct but share some genetic features, suggesting that patient-specific factors influence tumour formation.
- Suzanne S. Fei
- , Asia D. Mitchell
- & Paul T. Spellman
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Article
| Open AccessThe somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes
Much effort has recently been devoted to understanding the genomics of breast cancer. In this study, the authors integrate somatic mutation data with previously published copy number aberration and gene expression information for nearly 2,500 breast cancer samples.
- Bernard Pereira
- , Suet-Feung Chin
- & Carlos Caldas
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Article
| Open AccessCommon genetic variation in ETV6 is associated with colorectal cancer susceptibility
Genome-wide association studies have been performed to identify genetic variants that are associated with susceptibility to colorectal cancer. Here, the authors expand on these studies and identify a variant that regulates the expression of ETV6 and find that over-expression of ETV6 blocks cell proliferation in vitro.
- Meilin Wang
- , Dongying Gu
- & Jinfei Chen
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Article
| Open AccessThe topography of mutational processes in breast cancer genomes
Mutational signatures provide evidence of the mechanism of action of a given mutagen and are found in cancer cells. Here, using 560 breast cancer genomes, the authors demonstrate that mutational signatures are frequently associated with genomic architecture including nucleosome positioning and replication timing.
- Sandro Morganella
- , Ludmil B. Alexandrov
- & Serena Nik-Zainal
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Article
| Open AccessIdentification of four novel susceptibility loci for oestrogen receptor negative breast cancer
Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.
- Fergus J. Couch
- , Karoline B. Kuchenbaecker
- & Antonis C. Antoniou
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Article
| Open AccessIntegrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas
Oligodendroglial tumours are characterized into three different molecular subtypes. Here, the authors use genomic data to identify a further three subgroups of 1p/19q co-deleted tumours and demonstrate an association with an aggressive phenotype.
- Aurélie Kamoun
- , Ahmed Idbaih
- & Chiara Villa
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Article
| Open AccessSpatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Diffuse Intrinsic Pontine Gliomas are diagnosed by sampling a small portion of the tumour. Here, using multiple samples from tumours, the authors analyse the spatial and temporal distribution of driver mutations revealing that H3K27M mutations arise first in tumorigenesis followed by a specific invariable sequence of driver mutations, which are homogeneously distributed across the tumour mass.
- Hamid Nikbakht
- , Eshini Panditharatna
- & Javad Nazarian
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Article
| Open AccessDifferential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy
Oesophageal adenocarcinoma is often treated with chemotherapy before surgery. Here, the authors sequence cancer samples before and after chemotherapy and examine how the genome changes, focusing on changes in driver gene mutations and differential clonal evolution between good and poor responders.
- John M. Findlay
- , Francesc Castro-Giner
- & Ian Tomlinson
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Correspondence
| Open AccessCorrespondence: Reply to ‘SEMA4A variation and risk of colorectal cancer’
- Heinz Sill
- , Eduard Schulz
- & C. Richard Boland
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Correspondence
| Open AccessCorrespondence: SEMA4A variation and risk of colorectal cancer
- Ben Kinnersley
- , Daniel Chubb
- & Richard S. Houlston
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Article
| Open AccessMeta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPPassociated with risk of this disease.
- Sonja I. Berndt
- , Nicola J. Camp
- & Susan L. Slager
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Article
| Open AccessMultiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice
CRISPR/Cas9 technology has been used for genome engineering in vivo. Here, the authors use a transfection technique to deliver multiple guide RNAs to the pancreas of adult mice, allowing genetic screening and chromosome engineering in pancreatic cancer.
- Roman Maresch
- , Sebastian Mueller
- & Roland Rad
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Article
| Open AccessMutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents
Chronic myelomonocytic leukaemia is treated with agents that modify DNA methylation but whether they have direct cytotoxic effects is unclear. Here, the authors show that cells from treated patients show marked methylation changes without altered somatic mutation burden, suggesting that cytotoxicity is not a major factor in therapeutic efficacy.
- Jane Merlevede
- , Nathalie Droin
- & Eric Solary
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Article
| Open AccessDiverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells
Cancer cells that survive initial drug treatment can persist in the presence of drugs. Here, the authors generate persister cells that are resistant to the EGFR tyrosine kinase inhibitor erlotinib and show by single cell analysis that multiple mechanism give rise to the drug-resistant persister state.
- Michael Ramirez
- , Satwik Rajaram
- & Steven J. Altschuler
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Article
| Open AccessA variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology
A risk variant located at 9p21.3 is associated with cancer risk in pediatric B-cell precursor acute lymphoblastic leukaemia. Here, the authors show that this variant affects the gene expression of the tumour suppressor gene Cdkn2b.
- Eric A. Hungate
- , Sapana R. Vora
- & Kenan Onel
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Article
| Open AccessKRAS insertion mutations are oncogenic and exhibit distinct functional properties
Amino acid substitutions in K-Ras that constitutively activate the protein are common in cancer. Here, the authors describe mutations in the K-RasSwitch 2 domain and show that the mutant proteins accumulate in the active conformation, exhibit defective binding to PI3 kinase, and are hypersensitive to MEK inhibitors.
- Yasmine White
- , Aditi Bagchi
- & Ari J. Firestone
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Article
| Open AccessCancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage
Mutations in the splicing factor SF3B1 are found in uveal melanoma. Here, Alsafadi et al. use RNA-sequencing data from these cancers and experimental models, and show that mutant SF3B1 promotes alternative branchpoints in a specific gene subset and that the mutant protein gains a new function.
- Samar Alsafadi
- , Alexandre Houy
- & Marc-Henri Stern
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Article
| Open AccessFunctional annotation of rare gene aberration drivers of pancreatic cancer
Next generation sequencing allows the identification of oncogenic driver genes in pancreatic cancer. Here, in an effort to identify additional causal genes, the authors develop a high throughput in vivoscreen and identify genes that whilst infrequently mutated in pancreatic cancer contribute to tumour formation.
- Yiu Huen Tsang
- , Turgut Dogruluk
- & Kenneth L. Scott
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Article
| Open AccessGenome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma
The prognosis of multiple myeloma patients varies widely. Here, to identify genetic factors associated with differing prognoses, the authors carried out a meta-analysis of four genome-wide association studies and identified a risk variant associated with survival interval.
- David C. Johnson
- , Niels Weinhold
- & Gareth J. Morgan
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Article
| Open AccessPatterns and functional implications of rare germline variants across 12 cancer types
Published sequencing data sets of cancer samples could be used to identify genetic variants associated with the risk of developing cancer. Here, Luet al. analyse over 4,000 tumour-normal pairs to reveal variable frequencies of inherited susceptibilities across 12 cancer types and find enrichment of functionally validated missense variants of unknown significance.
- Charles Lu
- , Mingchao Xie
- & Li Ding
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Article
| Open AccessHypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts
Smoking tobacco is known to alter DNA methylation. Here, the authors show that hypomethylation of smoke-related genes is associated with future increase in lung cancer risk.
- Francesca Fasanelli
- , Laura Baglietto
- & Paolo Vineis
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Article
| Open AccessA comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing
Cancer genetics has benefited from the advent of next generation sequencing, yet a comparison of sequencing and analysis techniques is lacking. Here, the authors sequence a normal-tumour pair and perform data analysis at multiple institutes and highlight some of the pitfalls associated with the different methods.
- Tyler S. Alioto
- , Ivo Buchhalter
- & Ivo G. Gut
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Article
| Open AccessFrequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas
Despite lung adenocarcinoma having a high global mortality, the genetic mutations present in Asian patients are uncharacterized. Here the authors use genomic and transcriptomic analysis to identify thirteen significantly affected genes, including RHPN2, GLI3, MRC2, TP53 and IQGAP3.
- Kui Wu
- , Xin Zhang
- & Jianxing He
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Article
| Open AccessWhole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
The oncogenic events driving indolent chronic lymphocytic leukaemia are relatively unknown. Here, the authors perform whole genome sequencing on 30 such tumours and identify recurrent mutations in IGLL5and two activation induced cytidine deaminase signatures that are operative at different stages of CLL evolution.
- S. Kasar
- , J. Kim
- & J. R. Brown
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Article
| Open AccessMLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours
Wilms tumour is a rare renal neoplasm that primarily affects children but the genomic changes responsible for its development are currently largely unknown. In this study, the authors identify somatic mutations of the MLLT1gene that are potentially involved in the aetiology of a subset of Wilms tumours.
- Elizabeth J. Perlman
- , Samantha Gadd
- & Malcolm A. Smith
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Article
| Open AccessExome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency
Osteosarcomas are a heterogenous group of tumours and little is known about how these tumours evolve. Here, Kovac et al. use exome sequencing and discover that although no driver gene explains the majority of these tumours, they are characterized by specific mutation signatures and genomic instability typical of BRCA1/2-deficient tumours.
- Michal Kovac
- , Claudia Blattmann
- & Daniel Baumhoer
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Article
| Open AccessDifferential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion
How breast cancer cells adapt to individual therapies targeting the oestrogen receptor alpha is poorly understood. Here the authors show resistance emerging through differential epigenetic reprogramming that activates the cholesterol biosynthesis pathway.
- Van T. M. Nguyen
- , Iros Barozzi
- & Luca Magnani
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Article
| Open AccessIdentification of candidate genes for prostate cancer-risk SNPs utilizing a normal prostate tissue eQTL data set
Single nucleotide polymorphisms—SNPs—have been identified for prostate cancer but whether these SNPs alter the expression of genes is largely unknown. In this study, the authors search for genes located within 2 Mb of the SNPs and identify SNPs that influence gene expression, so called expression quantitative trait loci.
- S. N. Thibodeau
- , A. J. French
- & D J. Schaid
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Article
| Open AccessAcute loss of TET function results in aggressive myeloid cancer in mice
TET dioxygenases are known to have tumour suppressor activity. Here, An et al. show that Tet2/Tet3 double conditional mutant mice develop aggressive myeloid leukaemia, and suggest that rather than increased DNA methylation, aberrant gene expression and defects in DNA damage response and repair are the major drivers of myeloid leukaemogenesis upon TET loss-of-function.
- Jungeun An
- , Edahí González-Avalos
- & Anjana Rao