Featured
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| Open AccessDeterminants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci
The role of non-coding mutations in cancer progression and immune evasion needs to be further explored. Here, the authors investigate the potential of common somatic and germline 3′ untranslated region variants in predicting response to immunotherapy in gastric patients.
- Christos Miliotis
- , Yuling Ma
- & Ioannis S. Vlachos
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Article
| Open AccessIntegrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis
While it is known that localised prostate cancer is characterised by clonal heterogeneity, the clonal origin of synchronous lymph node (LN) metastases remains poorly understood. Here, the authors analyse the clonal origin of LN metastases in prostate cancer patients using multi-region sequencing.
- Udit Singhal
- , Srinivas Nallandhighal
- & Simpa S. Salami
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Article
| Open AccessAn improved epigenetic counter to track mitotic age in normal and precancerous tissues
DNA methylation (DNAm) clocks can track mitotic age, but their potential use for cancer risk prediction remains less explored. Here, the authors develop a DNAm counter of total mitotic age (stemTOC) that shows an increase of mitotic age in normal tissues and precancerous lesions.
- Tianyu Zhu
- , Huige Tong
- & Andrew E. Teschendorff
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Article
| Open AccessWhole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers
Efforts to allow routine whole genome and transcriptome analysis (WGTA) for pediatric cancers in the clinic remain critical. Here, the authors present results of a unified genomics and bioinformatics pipeline for WGTA in paediatric cancers, the Personalized OncoGenomics (POG) program, with a focus on potential therapeutic targets.
- Rebecca J. Deyell
- , Yaoqing Shen
- & Shahrad R. Rassekh
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Article
| Open AccessBone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes
Bone marrow stromal cells (BMSCs) are known to promote the development of drug resistance. Here, the authors investigate the chromatin remodeling and associated changes in gene expression in the multiple myeloma (MM) cells following their interactions with BMSCs, which are also observed in extramedullary disease (EMD).
- Moritz Binder
- , Raphael E. Szalat
- & Nikhil C. Munshi
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Article
| Open Access1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma
Translocations and copy number variations that affect multiple myeloma (MM) have not been investigated at the single cell level. Here, single cell multi-omics reveal the relationship between epigenetic regulation and cytogenetic events that lead to the increase of cell proliferation in MM.
- Travis S. Johnson
- , Parvathi Sudha
- & Brian A. Walker
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Article
| Open AccessDisentangling oncogenic amplicons in esophageal adenocarcinoma
Esophageal adenocarcinoma is characterised by frequent amplifications in oncogenes. Here, the authors use short- and long-read sequencing approaches to analyze primary tumor samples and tumour-derived organoids and to investigate the mechanisms underlying complex amplifications.
- Alvin Wei Tian Ng
- , Dylan Peter McClurg
- & Rebecca C. Fitzgerald
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Article
| Open AccessSystematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types
Single-cell sequencing has enabled detailed analyses of the tumour microenvironment (TME). Here, the authors perform an integrative analysis of the TME using single-cell and spatial transcriptomics data from over a thousand tumours across thirty cancer types, identifying interferon-enriched community states predictive of immunotherapeutic responses.
- Junho Kang
- , Jun Hyeong Lee
- & Jong-Eun Park
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Article
| Open AccessPervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs
By applying Hi-C to cells derived from the tumors of 24 GBM patients, the authors show pervasive structural variation in GBM chromosomal organization. How such patient-to-patient variation explains the characteristic gene expression patterns in each tumor is investigated.
- Ting Xie
- , Adi Danieli-Mackay
- & Argyris Papantonis
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Article
| Open AccessThe genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans
Mouse models often combine mutant alleles to accelerate cancer development, limiting oncogenic diversity. Here the authors show that sporadic MYC activation in Vk*MYC mice is sufficient to induce tumors with a variety of secondary mutations that mirror the genetic heterogeneity of human myeloma.
- Francesco Maura
- , David G. Coffey
- & Marta Chesi
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Article
| Open AccessA human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations
Copy number alterations in stem cells impair neural crest differentiation and set the stage for neuroblastoma-like traits and tumours. This study hints at early tumourigenesis mechanisms and finds developmental gene signatures linked to prognosis.
- Ingrid M. Saldana-Guerrero
- , Luis F. Montano-Gutierrez
- & Florian Halbritter
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Article
| Open AccessInvestigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment
The effect of noncoding genetic variation on acute lymphoblastic leukemia treatment response is not fully understood. Here, the authors functionally evaluated variants associated with pharmacological traits and validate the role of rs1247117 in gene regulation impacting therapeutic response.
- Kashi Raj Bhattarai
- , Robert J. Mobley
- & Daniel Savic
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Article
| Open AccessIdentifying tumor type and cell type-specific gene expression alterations in pediatric central nervous system tumors
The molecular features of paediatric central nervous system (CNS) tumours are not fully understood, posing a challenge for targeted therapies. Here, the authors characterise paediatric CNS tumours using single-nucleus RNA-seq; they identify cell type populations associated with specific tumour types and with response to therapy.
- Min Kyung Lee
- , Nasim Azizgolshani
- & Brock C. Christensen
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Article
| Open AccessAssociations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors
Cell type-specific epigenomic alterations and heterogeneity in paediatric central nervous system (CNS) tumours remain underexplored. Here, the authors integrate bulk DNA cytosine modification data with bulk and single-nucleus RNA-sequencing to explore cell type-specific epigenomic alterations and gene regulation in paediatric CNS tumours.
- Min Kyung Lee
- , Nasim Azizgolshani
- & Brock C. Christensen
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Article
| Open AccessA case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID
Leukaemia development has been reported as an associated risk of haematopoietic stem cell gene therapy (HSPC-GT) using retroviral vectors in different diseases. Here, the authors show a case of T-cell acute lymphoid leukaemia in a patient with Adenosine Deaminase-deficient Severe Combined Immunodeficiency (ADA-SCID) treated with retroviral gene therapy.
- Daniela Cesana
- , Maria Pia Cicalese
- & Alessandro Aiuti
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Article
| Open AccessEZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition
Cells carrying EZH2 mutations found in lymphoma show a specific transcriptional response to PRC2 inhibition. A longitudinal study reveals unexpected genetic heterogeneity in follicular lymphomas, with implications for therapeutic strategies.
- Pierre Romero
- , Laia Richart
- & Raphaël Margueron
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Article
| Open AccessHigh clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue
It remains challenging to characterise somatic copy number alterations (SCNAs) in tumors and the surrounding tissues with spatial and single-cell resolution. Here, the authors develop the scCUTseq approach to characterise SCNAs from single cells in multi-region prostate cancer samples and identify pseudo-diploid cells and subclones.
- Ning Zhang
- , Luuk Harbers
- & Nicola Crosetto
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Article
| Open AccessUveal melanoma immunogenomics predict immunotherapy resistance and susceptibility
Metastatic uveal melanoma is poorly responsive to immune checkpoint inhibition. Here, the authors analyse 100 uveal melanoma metastases using bulk and single cell RNA-seq, TCR analysis, and immune reactivity to show potent, yet, quiescent tumour infiltrating lymphocytes that can be harnessed by adoptive transfer to confer tumour immunity.
- Shravan Leonard-Murali
- , Chetana Bhaskarla
- & Udai S. Kammula
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Article
| Open AccessIntegrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks
Papillary thyroid cancers (PTC) generally have good prognosis, but their recurrence rate remains high. Here, the authors use proteogenomics and metabolomics to identify molecular features in PTC tumours and determine PTC subtypes that are associated with prognosis and potential targeted therapies.
- Ning Qu
- , Di Chen
- & Rongliang Shi
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Article
| Open AccessTumor phylogeography reveals block-shaped spatial heterogeneity and the mode of evolution in Hepatocellular Carcinoma
Hepatocellular carcinomas (HCC) present spatial intratumour heterogeneity (sITH). Here, the authors perform a genomic and phylogenetic analysis of spatially-sampled HCC tumour sections, observe block-shaped sITH, and find ongoing natural selection where ancestral and derived clones spatially compete in the same tumor.
- Xiaodong Liu
- , Ke Zhang
- & Weiwei Zhai
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Article
| Open AccessSingle-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma
Hepatoblastoma (HB) is the most frequent paediatric liver tumour with heterogeneous cellular phenotypes that influence clinical outcomes. Here, the authors integrate bulk, single-cell, and spatial multi-omics to characterise HB cells, and find that clonal evolution and epigenetic plasticity shape response to therapy.
- Amélie Roehrig
- , Theo Z. Hirsch
- & Eric Letouzé
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Article
| Open AccessAccelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation
Here the authors find that erythroblasts of myelodysplastic syndromes with SF3B1 mutation leading to inefficient erythropoiesis show DNA replication stress with accelerated forks and reduced R-loops. Restoring R-loops by a histone deacetylase inhibitor rescues erythroid differentiation.
- David Rombaut
- , Carine Lefèvre
- & Michaela Fontenay
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Article
| Open AccessFinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA
DNA methylation from cell-free DNA (cfDNA) can be profiled using whole genome bisulfite sequencing (WGBS). Here, the authors develop a computational method, FinaleMe, that predicts DNA methylation and tissues of-origin in cfDNA and validate its performance using paired deep and shallow-coverage whole-genome sequencing (WGS) and WGBS data.
- Yaping Liu
- , Sarah C. Reed
- & Manolis Kellis
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Article
| Open AccessIdentification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms
The current stratification of Intraductal Papillary Mucinous Neoplasms (IPMN) is based on clinical and histological features rather than molecular ones. Here, the authors use spatial transcriptomics to characterise IPMN patient samples, and identify markers associated with progression to pancreatic cancer.
- Antonio Agostini
- , Geny Piro
- & Carmine Carbone
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Article
| Open AccessComprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants
EGFR mutations are frequent in glioblastoma and lung cancer. Here, the authors perform deep mutational scanning of EGFR, followed by a high-throughput functional screen and analysis of patient data, to identify variants with differing sensitivities to a range of EGFR tyrosine kinase inhibitors.
- Tikvah K. Hayes
- , Elisa Aquilanti
- & Matthew Meyerson
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Article
| Open AccessPhenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers
Mendelian randomisation can identify potential risk factors from large populations. Here, the authors analyse 3000 traits across multiple cancer types to search for potential risk factors and molecular biomarkers.
- Molly Went
- , Amit Sud
- & Richard Houlston
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Article
| Open AccessAberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma
The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression.
- Daniel A. Ang
- , Jean-Michel Carter
- & Yinghui Li
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Article
| Open AccessAllele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells
Quantifying the impact of copy-number alterations (CNAs) on gene expression at the subclone level in cancer remains a challenge. Here, the authors develop TreeAlign, a method that integrates sample-matched single-cell DNA and RNA sequencing data to infer the impact of CNAs on subclonal gene expression.
- Hongyu Shi
- , Marc J. Williams
- & Sohrab P. Shah
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Article
| Open AccessExemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial
Intrinsic and acquired resistances to CDK4/6 inhibitors have been described in patients with breast cancer. Here the authors report the results from a phase I/II clinical trial of the aromatase inhibitor exemestane plus everolimus (mTOR inhibitor) and palbociclib (CDK4/6i) in patients with metastatic breast cancer, assessing safety, clinical efficacy, as well as genomic and transcriptomic determinants of resistance.
- Jorge Gómez Tejeda Zañudo
- , Romualdo Barroso-Sousa
- & Nikhil Wagle
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| Open AccessMesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes
Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer. This study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their substrate selectivity.
- Ambrocio Sanchez
- , Pedro Ortega
- & Rémi Buisson
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Article
| Open AccessThe evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis
Detailed molecular studies are required to understand the differences between primary and metastatic upper tract urothelial carcinoma (UTUC). Here, the authors use genomics, transcriptomics and imaging mass cytometry to characterise the molecular profiles of primary and metastatic UTUC, and find that molecular subtypes remain highly conserved.
- Kentaro Ohara
- , André Figueiredo Rendeiro
- & Juan Miguel Mosquera
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Article
| Open AccessSpatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma
Macrophages are abundant in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Here, the authors use spatial transcriptomics to characterize macrophages in DLBCL and reactive lymphoid tissues, and propose six spatially-derived macrophage signatures that are associated with features like cell of origin and clinical outcomes.
- Min Liu
- , Giorgio Bertolazzi
- & Anand D. Jeyasekharan
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Article
| Open AccessComprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation
The benefit of hyperthermic intraperitoneal chemotherapy in epithelial ovarian cancer remains controversial. Here, the authors perform a multi-omics analysis of hyperthermia-treated ovarian cancer cells, show that CDK1 becomes hyperactivated and regulates signalling upon hyperthermia, and identify WEE1 as a synergistic therapeutic target for hyperthermic intraperitoneal therapy.
- Xiaohang Yang
- , Xingyuan Hu
- & Chaoyang Sun
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Article
| Open AccessEvolving copy number gains promote tumor expansion and bolster mutational diversification
Understanding the timing and fitness of somatic copy number alterations (SCNAs) in cancer would shed light on cancer progression and evolution. Here, the authors develop Butte, a computational framework to estimate the timing of clonal SCNAs that encompass multiple gains, and apply it on whole-genome sequencing data from 184 samples.
- Zicheng Wang
- , Yunong Xia
- & Ruping Sun
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Article
| Open AccessDomain generalization enables general cancer cell annotation in single-cell and spatial transcriptomics
Efficient and accurate annotation of malignant cells is crucial for single-cell and spatial transcriptomics in cancer. Here, the authors develop Cancer-Finder, a deep-learning algorithm that can identify malignant cells in cancer single-cell and spatial transcriptomics data with speed and precision.
- Zhixing Zhong
- , Junchen Hou
- & Jia Song
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Article
| Open AccessThe evolutionary impact of childhood cancer on the human gene pool
Pathogenic germline variants associated with childhood cancer risk could be subject to evolutionary constraints. Here, the authors analyse publicly available germline data in large cohorts and observe that paediatric cancer predisposition syndrome genes are highly constrained in the general population.
- Ulrik Kristoffer Stoltze
- , Jon Foss-Skiftesvik
- & Kjeld Schmiegelow
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Article
| Open AccessA Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE
Alterations of therapeutic pressures have been shown to affect clonal evolution of resistance. Here, the authors conducted a single arm, phase 2 trial consisting of alternating osimertinib and gefitinib in non-small cell lung cancer, and found ctDNA dynamics were predictive of response.
- Lavinia Tan
- , Chris Brown
- & Benjamin J. Solomon
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Article
| Open AccessPrediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer
Metastatic castration-resistant prostate cancer is a highly aggressive disease, with a variable response to treatment. Here, the authors validate ctDNA fraction as a poor prognostic factor and develop a model to predict whether patients harbor sufficient ctDNA for informative blood-based genotyping.
- Nicolette M. Fonseca
- , Corinne Maurice-Dror
- & Alexander W. Wyatt
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Article
| Open AccessMulti-dimensional scaling techniques unveiled gain1q&loss13q co-occurrence in Multiple Myeloma patients with specific genomic, transcriptional and adverse clinical features
The characterisation of the molecular features of multiple myeloma (MM) remains challenging. Here, the authors identify a subset of MM patients with a dismal clinical outcome, harbouring both chromosomes 1q CN gain and 13 CN loss and overexpressing CCND2.
- Carolina Terragna
- , Andrea Poletti
- & Michele Cavo
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Article
| Open AccessMachine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer
‘Extrachromosomal DNA has been previously linked to tumour progression and heterogeneity, but its potential as a cancer biomarker has not been fully explored. Here, the authors develop a computational framework to refine genomic subtypes and predict response to immunotherapy in gastrointestinal cancer.
- Shixiang Wang
- , Chen-Yi Wu
- & Qi Zhao
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Article
| Open AccessCellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia
The cellular hierarchies in acute promyelocytic leukemia (APL) remain to be explored. Here, the authors perform single-cell RNA sequencing of 16 APL patients to characterise its cellular composition and develop an APL-specific stemness score for assessing the risk of early death in APL.
- Wen Jin
- , Yuting Dai
- & Kankan Wang
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Article
| Open AccessExperimental evidence for cancer resistance in a bat species
Bats have been suggested to be resistant to cancer due to mechanisms related to their evolved longevity, but the associated molecular drivers are still understudied. Here, the authors examine cancer resistance mechanisms across seven bat species using in vitro and in vivo models, and identify HIF1A, COPS5, and RPS3 as related genes.
- Rong Hua
- , Yuan-Shuo Ma
- & Zhen Liu
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Article
| Open AccessIntegrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types
Here the authors identify gene targets and causal cell types affected by genetic risk loci in uterine fibroids by combining meta-analysis on existing fibroid genome-wide association studies and integrated the identified risk loci and potentially causal single nucleotide polymorphisms with epigenomics, transcriptomics, 3D chromatin organization from diverse cell types as well as primary uterine fibroids patient’s samples.
- Kadir Buyukcelebi
- , Alexander J. Duval
- & Mazhar Adli
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Article
| Open AccessA clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1
In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.
- Ling Hai
- , Dirk C. Hoffmann
- & Tobias Kessler
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Article
| Open AccessTransposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
It has been suggested that transposable elements (TE) play a role in tumourigenesis, but the associated mechanisms remain unclear. Here, the authors show, using colorectal cancer data and Bayesian Networks, that TEs can mediate the effect of expression quantitative trait loci and contribute to the regulation of cancer-related genes.
- Nikolaos M. R. Lykoskoufis
- , Evarist Planet
- & Emmanouil T. Dermitzakis
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Article
| Open AccessClinical application of tumour-in-normal contamination assessment from whole genome sequencing
Assessing tumour contamination in normal samples is critical for accurate variant calling in cancer samples. Here, the authors develop TINC, a computational method to determine the level of tumour in normal contamination, and demonstrate its application in the Genomics England 100,000 Genomes Project dataset.
- Jonathan Mitchell
- , Salvatore Milite
- & Giulio Caravagna
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Article
| Open AccessFunctional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance
The molecular mechanisms underlying malignant transformation of the Schwann lineage in Schwann cell tumours remain to be explored. Here, the authors suggest that NF2 inactivation leads to PAK activation leading to NF1-mutant Schwann cell tumour de-differentiation and resistance to selumetinib.
- Harish N. Vasudevan
- , Emily Payne
- & David R. Raleigh
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Article
| Open AccessEpigenetic reprogramming shapes the cellular landscape of schwannoma
Schwannomas are regularly treated with radiotherapy, but the molecular effects on these tumours and their microenvironment remain unclear. Here, the authors show that radiotherapy can induce epigenetic reprogramming and immune infiltration in schwannomas, and develop the snARC-seq approach to analyse the epigenomic evolution at the single-cell level.
- S. John Liu
- , Tim Casey-Clyde
- & David R. Raleigh
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Article
| Open AccessMechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC
Heterogeneous response to Enzalutamide remains a critical issue in castration-resistant prostate cancer (CRPC). Here, the authors reconstruct a CRPC-specific mechanism-centric regulatory network to identify signatures of Enzalutamide response and predict patients at risk of Enzalutamide resistance.
- Sukanya Panja
- , Mihai Ioan Truica
- & Antonina Mitrofanova