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Article
| Open Access
Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states
Glioblastoma (GBM) cells can infiltrate into the tumour microenvironment (TME) and contribute to recurrence. Here, the authors analyse primary and recurrent GBMs and their TME using single-nucleus and spatial transcriptomics, revealing tissue states defined by the combinations of neoplastic and non-neoplastic cells, which could be therapeutic targets.
- Osama Al-Dalahmah
- , Michael G. Argenziano
- & Peter Canoll
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Article
| Open Access
Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients
Xeroderma pigmentosum (XP) is a rare genetic disorder that is associated with a higher risk of skin cancer. Here, the authors analyse the genomes of skin cancers from patients across five different XP groups, revealing genetic and molecular factors related to the mutational profile and UV-related mutagenesis in XP.
- Andrey A. Yurchenko
- , Fatemeh Rajabi
- & Sergey I. Nikolaev
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| Open Access
3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma
Ependymoma is a tumor of the brain or spinal cord with the two most common and aggressive types mainly occurring in children. Here the authors employ 3D genomics and epigenomics to reveal targets for aggressive ependymoma tumors in children.
- Konstantin Okonechnikov
- , Aylin Camgöz
- & Lukas Chavez
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| Open Access
Bladder cancer organoids as a functional system to model different disease stages and therapy response
Bladder cancer heterogeneity can limit treatment efficacy in individual patients. Here, the authors use patient derived organoids to develop a drug screening pipeline and identify markers of treatment response.
- Martina Minoli
- , Thomas Cantore
- & Marianna Kruithof-de Julio
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| Open Access
Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA
Despite advances in ctDNA cancer detection, early detection remains difficult. Here, the authors utilise whole genome sequencing of 2,125 patient samples to create a model for early cancer and tissue of origin detection.
- Mingyun Bae
- , Gyuhee Kim
- & Jung Kyoon Choi
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Article
| Open Access
Predicting response to enzalutamide and abiraterone in metastatic prostate cancer using whole-omics machine learning
Prostate cancer is known to have a variable response to androgen receptor signalling inhibitors. Here, the authors use machine learning to predict response to therapy from genomic, transcriptomic and clinical data.
- Anouk C. de Jong
- , Alexandra Danyi
- & Martijn P. Lolkema
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Article
| Open Access
Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBPα activation as a mechanism of FLT3i resistance and therapeutically target C/EBPα activation in combination with FLT3i in preclinical models FLT3-ITD AML.
- Hanlin Wang
- , Guanghao Luo
- & Jia Li
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Article
| Open Access
Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication
Oncogenic gene fusions are frequent in childhood cancers but remain poorly understood and untargeted. Here, the authors identify 272 oncogenic fusions in transcriptomics data from 5190 childhood cancer patients, revealing their possible etiologies, their links with tumor progression and evolution, and their potential as therapeutic targets.
- Yanling Liu
- , Jonathon Klein
- & Xiaotu Ma
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| Open Access
Comprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes
Duodenal cancer (DC) has complex subtypes and undergoes complicated morphological changes throughout progression, so understanding the molecular basis is crucial. Here, the authors perform a proteogenomics analysis of 156 DCs, revealing molecular subtypes as well as the roles of smoking, AARS1 and PARP1.
- Lingling Li
- , Dongxian Jiang
- & Chen Ding
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Article
| Open Access
Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
Tumour heterogeneity in clear cell renal cell carcinoma (ccRCC) remains to be investigated. Here, the integration of spatial omics, transcriptional and chromatin accessibility profiling at the single-nucleus level and bulk proteogenomics data reveal markers and pathways important for ccRCC.
- Yige Wu
- , Nadezhda V. Terekhanova
- & Feng Chen
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Article
| Open Access
Integrative proteogenomic characterization of early esophageal cancer
The progression of oesophageal squamous cell carcinoma (ESCC) from early to advanced stages requires comprehensive molecular characterisation. Here, the authors perform a proteogenomics analysis of ESCC patient samples across nine histopathological stages and three phases, identifying key alterations and paths for progression.
- Lingling Li
- , Dongxian Jiang
- & Chen Ding
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Article
| Open Access
Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia
High hyperdiploid acute lymphoblastic leukaemia (HeH ALL) is driven by nonrandom chromosomal gains, which have been suggested to arise early - even before birth. Here, the authors use single-cell whole genome sequencing and in silico modelling to show that HeH ALL aneuploidies could originate early and follow punctuated evolution.
- Eleanor L. Woodward
- , Minjun Yang
- & Kajsa Paulsson
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| Open Access
Genomic characterization of DICER1-associated neoplasms uncovers molecular classes
DICER1 syndrome is associated with a predisposition to multiple tumor types. Here, the authors identify and characterize 3 molecular subgroups of mesenchymal tumors with DICER1 mutations.
- Felix K. F. Kommoss
- , Anne-Sophie Chong
- & William D. Foulkes
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Article
| Open Access
Pan-cancer classification of single cells in the tumour microenvironment
The accuracy and granularity of classifying cell types in the tumour microenvironment (TME) from single-cell RNA-seq data is impacted by heterogeneity among cancer cells and similarities among functionally related immune cells. Here, the authors develop scATOMIC, a tumour and TME cell type classifier based on a hierarchical approach that can be applied to pan-cancer datasets.
- Ido Nofech-Mozes
- , David Soave
- & Sagi Abelson
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Article
| Open Access
Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer
Analysing the regulatory consequences of mutations and splice variants at large scale in cancer requires efficient computational tools. Here, the authors develop RegTools, a software package that can identify splice-associated variants from large-scale genomics and transcriptomics data with efficiency and flexibility.
- Kelsy C. Cotto
- , Yang-Yang Feng
- & Malachi Griffith
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| Open Access
Integrated transcriptome study of the tumor microenvironment for treatment response prediction in male predominant hypopharyngeal carcinoma
Many patients with hypopharyngeal carcinoma (HPC) do not respond to first-line combination therapy. Here, the authors analyse the tumour and the tumour microenvironment of HPC patients treated with combination therapy using single-cell RNA-seq, and train a classifier to distinguish responders based on cell type composition.
- Yang Zhang
- , Gan Liu
- & Zhigang Huang
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| Open Access
Towards routine chromosome-scale haplotype-resolved reconstruction in cancer genomics
The precise inference of structural variants (SVs) requires suitable sequencing technologies and computational tools. Here, in order to analyse SVs with haplotype resolution, the author applies high-resolution long-read sequencing and long-range Hi-C to a melanoma cell line and develops an efficient graph-based computational framework, pstools.
- Shilpa Garg
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Article
| Open Access
Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma
The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.
- Bruna Calsina
- , Elena Piñeiro-Yáñez
- & Mercedes Robledo
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Article
| Open Access
A variational algorithm to detect the clonal copy number substructure of tumors from scRNA-seq data
The inference of clonal architectures in cancer using single-cell RNA-seq data remains challenging. Here, the authors develop SCEVAN, a variational algorithm for copy number-based clonal structure inference in single-cell RNA-seq data that can characterise evolution and heterogeneity in the tumour and the microenvironment.
- Antonio De Falco
- , Francesca Caruso
- & Michele Ceccarelli
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Article
| Open Access
Single-cell transcriptome profiling of the stepwise progression of head and neck cancer
Head and neck squamous cell carcinomas (HNSCCs) undergo a stepwise progression from normal tissues. In order to better understand the molecular mechanisms behind such progression, here the authors profile HNSCC tumors at different stages using single-cell RNA-seq, and observe the role of interactions with the tumor microenvironment.
- Ji-Hye Choi
- , Bok-Soon Lee
- & Chul-Ho Kim
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Article
| Open Access
Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas
The spatial organisation of diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) remains to be investigated. Here, the authors integrate short-read and long-read spatial profiling of DMG and GBM to identify regulatory programs and cellular ecosystems in distinct glioma niches.
- Yanming Ren
- , Zongyao Huang
- & Yuan Wang
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Article
| Open Access
Reconstructing clonal tree for phylo-phenotypic characterization of cancer using single-cell transcriptomics
The functional changes of individual clones in single cell RNA sequencing (scRNA-seq) data remain elusive. Here, the authors develop PhylEx that integrates bulk genomics data with co-occurrences of mutations revealed by scRNA-seq data and apply it to high-grade serous ovarian cancer cell line and breast cancer datasets.
- Seong-Hwan Jun
- , Hosein Toosi
- & Jens Lagergren
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Article
| Open Access
Single-cell biological network inference using a heterogeneous graph transformer
Single-cell multi-omics and deep learning could lead to the inference of biological networks across specific cell types. Here, the authors develop DeepMAPS, a deep learning, graph-based approach for cell-type specific network inference from single-cell multi-omics data that is tested on healthy and tumour tissue datasets.
- Anjun Ma
- , Xiaoying Wang
- & Qin Ma
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Article
| Open Access
Reconstruction of the tumor spatial microenvironment along the malignant-boundary-nonmalignant axis
Delineating the cellular composition of tumour boundaries in spatial transcriptomics (ST) data is challenging. Here, the authors develop Cottrazm to integrate ST with histological imaging and single-cell data, identify the malignant and non-malignant tissue boundaries, deconvolute cell-type composition, and reconstruct cell type-specific gene expression profiles.
- Zhenzhen Xun
- , Xinyu Ding
- & Youqiong Ye
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Comment
| Open AccessLarge-scale genomic analyses reveal alterations and mechanisms underlying clonal evolution and immune evasion in esophageal cancer
Esophageal cancers feature distinct manifestations between and within patients which complicate precision diagnosis, prognosis, and patient care. New genomic and epigenomic research uncovers novel mechanisms underlying both inter- and intra-tumoral heterogeneity in esophageal cancer, with significant biological and translational implications.
- De-Chen Lin
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Article
| Open Access
Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing
It is essential to understand heterogeneity and evolution at different omics levels in oesophageal squamous cell carcinoma (ESCC). Here, the authors use multi-omics to analyse heterogeneity and evolution in ESCC patient samples, and characterise the levels of immune infiltration as well as selective pressure from the tumour microenvironment.
- Sijia Cui
- , Nicholas McGranahan
- & Shixiu Wu
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Article
| Open Access
Widespread perturbation of ETS factor binding sites in cancer
Few cancer drivers in non-coding regions have been identified so far. Here, the authors develop a transcription factor-aware burden test to predict non-coding variants and analyze the impact on transcription factor binding - especially ETS factors - as well as their impact on transcriptional activity.
- Sebastian Carrasco Pro
- , Heather Hook
- & Juan Ignacio Fuxman Bass
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Article
| Open Access
Genomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer
The intermediate states of the epithelial-to-mesenchymal transition (EMT) in cancer require further molecular characterisation. Here, the authors develop a method to evaluate EMT transformation and trajectories in cancer transcriptomics data, characterising EMT macro-states, including a hybrid state, and EMT hallmarks.
- Guidantonio Malagoli Tagliazucchi
- , Anna J. Wiecek
- & Maria Secrier
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Article
| Open Access
Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability
Group 3 medulloblastomas (MBs) have the worst prognosis amongst the subtypes of MBs and are associated with MYC amplifications. Here the authors identify that mutations in CTDNEP1 cause MYC activation, amplification, and genomic instability in this subtype of MBs.
- Zaili Luo
- , Dazhuan Xin
- & Q. Richard Lu
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Article
| Open Access
Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer
Implementing high-throughput single-cell DNA sequencing for the study of solid tumours has been challenging. Here, the authors present an optimised approach for snap-frozen tissue single nuclei extraction and DNA sequencing, which can be applied to study pancreatic ductal adenocarcinoma evolution and heterogeneity.
- Haochen Zhang
- , Elias-Ramzey Karnoub
- & Christine A. Iacobuzio-Donahue
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Article
| Open Access
Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia
The PML-RARA gene fusion is the characteristic driver of Acute Promyelocytic Leukaemia (APL) and is known to bind to the genome. Here, the authors characterise the impact of PML-RARA on gene regulation in APL cell lines and patient samples using transcriptomics, epigenomics, and machine learning.
- William Villiers
- , Audrey Kelly
- & Cameron S. Osborne
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Article
| Open Access
Parallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT
Epithelial-to-mesenchymal transition (EMT) is a complex process regulated at multiple molecular levels. Here, the authors implement an analytic framework - PAMAF - to integrate data from twelve distinct omics modalities, which they use to understand the molecular changes and regulation during EMT in vitro.
- Indranil Paul
- , Dante Bolzan
- & Andrew Emili
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Article
| Open Access
Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers
In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.
- James J. Harding
- , Sarina A. Piha-Paul
- & Ghassan K. Abou-Alfa
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Article
| Open Access
Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance
It is critical to understand the factors that are associated with nasopharyngeal carcinoma (NPC) progression, metastasis and response to therapy. Here, the authors analyse primary and metastatic NPC samples using bulk and single-cell sequencing, and find two distinct evolutionary routes that lead to metastasis.
- Mei Lin
- , Xiao-Long Zhang
- & Ming-Yuan Chen
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Article
| Open Access
Estimation of cell lineages in tumors from spatial transcriptomics data
Cell type deconvolution in tumor spatial transcriptomics (ST) data remains challenging. Here, the authors develop Spatial Cellular Estimator for Tumors (SpaCET) to infer cell types and intercellular interactions from ST data in cancer across different platforms, with improved performance over similar methods.
- Beibei Ru
- , Jinlin Huang
- & Peng Jiang
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Article
| Open Access
Chromatin complex dependencies reveal targeting opportunities in leukemia
Epigenetic regulators are potential therapeutic drug targets in leukemia. Here, the authors perform combinatorial CRISPR knockouts to test gene-gene pairings in leukemia cells to discover compensatory non-lethal or synergistic lethal combinations with therapeutic potential.
- Fadi J. Najm
- , Peter DeWeirdt
- & Bradley E. Bernstein
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| Open Access
Decision level integration of unimodal and multimodal single cell data with scTriangulate
Single-cell genomics has expanded to measure diverse molecular modalities within the same cell. Here the authors provide a computational framework called scTriangulate to integrate cluster annotations from diverse independent sources, algorithms, and modalities to define statistically stable populations.
- Guangyuan Li
- , Baobao Song
- & Nathan Salomonis
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Article
| Open Access
DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer
Nail polish dryers commonly emit ultraviolet A (UVA) light, but the effects of this irradiation on mammalian cells remain unclear. Here, the authors examine the effects of UVA irradiation by a nail polish dryer on the genomes of mammalian cell lines, finding high levels of reactive oxygen species and related mutational signatures.
- Maria Zhivagui
- , Areebah Hoda
- & Ludmil B. Alexandrov
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Article
| Open Access
Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers
Colitis-associated cancers (CACs) develop in patients with inflammatory bowel disease and have distinct genomic features compared to sporadic colorectal cancers. Here, the authors characterize the genomic alterations of CAC tumors and dysplasia, finding decreased Wnt signaling and a lack of shared early genetic steps.
- Walid K. Chatila
- , Henry Walch
- & Rona Yaeger
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Article
| Open Access
Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis
Li-Fraumeni syndrome (LFS) is associated with pathogenic germline TP53 variants and predisposes patients to cancer; understanding the evolution and drivers of LFS-related tumours remains crucial. Here, the authors analyse 22 LFS tumours using whole-genome sequencing and reconstruct the evolution and timing of somatic driver alterations.
- Nicholas Light
- , Mehdi Layeghifard
- & Adam Shlien
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Article
| Open Access
A Bayesian model for unsupervised detection of RNA splicing based subtypes in cancers
RNA splicing variations could help identify cancer subtypes, but this task is computationally challenging. Here, the authors develop CHESSBOARD, a Bayesian tile finding algorithm for splicing data which identifies patterns in the form of tiles and can discover leukemia subgroups associated with therapeutic response.
- David Wang
- , Mathieu Quesnel-Vallieres
- & Yoseph Barash
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Article
| Open Access
Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer
Multiregion sequencing is needed to better capture the heterogeneity of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Here, the authors analyse HCC and iCCA tumours with multiregion single-cell RNA-seq, revealing cellular dynamics and communication networks with immune cells.
- Lichun Ma
- , Sophia Heinrich
- & Xin Wei Wang
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Article
| Open Access
Tissue and liquid biopsy profiling reveal convergent tumor evolution and therapy evasion in breast cancer
Liquid biopsies could be valuable tools to monitor breast cancer progression and evolution. Here, the authors investigate genomic profiling of tissue and liquid biopsies in a large cohort of patients with breast cancer during the course of therapy to characterise tumour evolution and acquired mutations.
- Smruthy Sivakumar
- , Dexter X. Jin
- & Ethan S. Sokol
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Article
| Open Access
A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
Nucleosome profiling from cell-free DNA (cfDNA) represents a potential approach for cancer detection and classification. Here, the authors develop Griffin, a computational framework for tumour subtype classification based on cfDNA nucleosome profiling that can work with ultra-low pass sequencing data.
- Anna-Lisa Doebley
- , Minjeong Ko
- & Gavin Ha
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Article
| Open Access
Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers
Acquired resistance can be associated with genetic changes, however, clinical molecular profiling is usually only considered at the time of diagnosis. Here, the authors use serial ctDNA profiling of 449 gastrointestinal cancers to demonstrate widespread tumour evolution associated with treatment resistance and its potential implications for treatment.
- David Hsiehchen
- , Leslie Bucheit
- & Hao Zhu
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Article
| Open Access
Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential
Epigenetic reprogramming of the androgen receptor (AR) has been identified as an important process driving prostate cancer (PCa) progression. Here, the authors analyze the role of AR chromatin binding heterogeneity in PCa clinical outcomes, metastasis and relapse.
- Jeroen Kneppers
- , Tesa M. Severson
- & Wilbert Zwart
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Article
| Open Access
Decoding molecular programs in melanoma brain metastases
Melanoma brain metastases (MBM) show heterogeneous therapeutic response determined by incompletely understood mechanisms. Here, the authors use a multi-OMICS approach and targeted sequencing (TargetSeq) to decipher programs that may define molecular subsets of MBM and their response to therapy.
- Josefine Radke
- , Elisa Schumann
- & Torben Redmer
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Article
| Open Access
Genomic disparities between cancers in adolescent and young adults and in older adults
The biological underpinnings underlying the increased mortality and morbidity in adolescents and young adults (AYA) remains poorly understood. Here, the authors investigate the clinical and genomic disparities in AYA and older adults in a cohort of more than 100,000 cancer patients.
- Xiaojing Wang
- , Anne-Marie Langevin
- & Siyuan Zheng
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Article
| Open Access
Evaluating cancer etiology and risk with a mathematical model of tumor evolution
Modelling how endogenous mutations accumulate in tissues is valuable to understand how cancers develop and evolve. Here, the authors establish a mathematical model that can predict the number of endogenous somatic mutations in the lifetime of tissues and approximate the time to cancer development.
- Sophie Pénisson
- , Amaury Lambert
- & Cristian Tomasetti
Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma