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| Open AccessSMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance
The molecular mechanisms involved in the development of SMARCB1-deficient renal medullary carcinomas (RMCs) remain to be characterised. Here, the authors integrated RMC omics data to show that ferroptosis resistance contributes to transformation of renal thick ascending limb cells into several RMC cell states.
- Bujamin H. Vokshi
- , Guillaume Davidson
- & Gabriel G. Malouf
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Article
| Open AccessGermline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response
The contribution of genetic factors to the tumour immune microenvironment (TIME) remains to be investigated. Here, the authors suggest the role of TIME eQTLs for target genes involved in reversing immune suppressive features.
- Meghana Pagadala
- , Timothy J. Sears
- & Hannah Carter
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Article
| Open AccessMapping the landscape of genetic dependencies in chordoma
Cancer cells possess unique molecular features that can confer an increased dependence on specific genes. Here, the authors use CRISPR-Cas9 screens to identify selectively essential genes and therapeutic targets in chordoma.
- Tanaz Sharifnia
- , Mathias J. Wawer
- & Stuart L. Schreiber
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Article
| Open AccessEtiology 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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Article
| Open AccessHistone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance
Alternative lengthening of telomeres (ALT) provides cancer cells a mechanism to sustain replicative immortality. Here, the authors identify KDM2A as a molecular vulnerability in ALT-dependent cancer cells and demonstrate its role in the resolution of ALT-specific telomere clusters via recruitment of SENP6.
- Fei Li
- , Yizhe Wang
- & Hongwu Zheng
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Article
| Open AccessGenomic 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 AccessA DNA tumor virus globally reprograms host 3D genome architecture to achieve immortal growth
The dynamic and temporal changes of host genome architecture during Epstein-Barr virus (EBV) transformation are not well known. Here the authors transform human primary B lymphocyte into lymphoblastoid cell lines (LCLs) with EBV and show that the host 3D genome is rewired to facilitate expression of key oncogenes.
- Chong Wang
- , Xiang Liu
- & Bo Zhao
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Article
| Open AccessSOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry
The development of neuroblastoma (NB) is regulated by multiple core transcription factors. Here, SOX11 is identified as a potential epigenetic master regulator upstream of the core regulatory circuitry in adrenergic high-risk neuroblastoma.
- Bieke Decaesteker
- , Amber Louwagie
- & Frank Speleman
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Article
| Open AccessNon-canonical functions of SNAIL drive context-specific cancer progression
SNAIL promotes tumour metastasis through inducing epithelial to mesenchymal transition (EMT). Here the authors report that SNAIL bypasses senescence and regulates cell cycle progression to promote pancreatic carcinogenesis and this is independent of EMT induction.
- Mariel C. Paul
- , Christian Schneeweis
- & Dieter Saur
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Article
| Open AccessA non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells
Mutations of ATRX are frequent in cancers that immortalize through the ALT (Alternative lengthening of telomeres) pathway. Here the authors show that ALT features are repressed in embryonic stem cells that lack ATRX but induced by continuous telomere instability triggered upon cell differentiation.
- Timothy K. Turkalo
- , Antonio Maffia
- & Dirk Hockemeyer
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Article
| Open AccessTracking 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 AccessMitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells
DNA replication stress can generate under-replicated DNA regions which is fixed by an atypical form of DNA repair synthesis in mitosis (MiDAS). Here the authors show that translesion and replicative DNA polymerases cooperate via the POLD3 subunit to complete MiDAS in human cells.
- Wei Wu
- , Szymon A. Barwacz
- & Ying Liu
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Article
| Open AccessMulti-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 AccessEvidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
Many genetic factors that contribute to uterine leiomyomata (UL) - the most common tumours of the female genital tract - remain to be discovered. Here, the authors conduct a UL meta-genome-wide association study, and find loci related to altered muscle tissue biology that are associated with UL.
- Eeva Sliz
- , Jaakko S. Tyrmi
- & Johannes Kettunen
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Article
| Open AccessThe NFIB/CARM1 partnership is a driver in preclinical models of small cell lung cancer
Protein arginine methylation can contribute to tumor progression. Here the authors show that protein arginine methyltransferase, CARM1, methylates transcription factor NFIB to promote the growth of small cell lung cancers.
- Guozhen Gao
- , Simone Hausmann
- & Mark T. Bedford
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Article
| Open AccessMiXcan: a framework for cell-type-aware transcriptome-wide association studies with an application to breast cancer
Conventional transcriptome-wide association study (TWAS) approaches predict genetically regulated gene expression at the tissue level. Here, the authors develop a framework for cell-type-aware TWAS that predicts cell-type level expression from genotype data and identifies disease-associated genes with cell-type-specific effects.
- Xiaoyu Song
- , Jiayi Ji
- & Weiva Sieh
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Article
| Open AccessDNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation
Cell free DNA is produced through a non-random process. Here, the authors use orientation-aware fragmentation analysis to identify DNA methylation as a regulator of nuclease function.
- Yunyun An
- , Xin Zhao
- & Kun Sun
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Article
| Open AccessSmarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma
Clinical management of pancreatic cancer remains challenging. Here, the authors suggest SMARCD3 as a potential epigenetic dependency establishing the metabolic landscape in aggressive pancreatic cancer cells and as a potential therapeutic target in pancreatic cancer.
- L. Paige Ferguson
- , Jovylyn Gatchalian
- & Tannishtha Reya
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Article
| Open AccessGermline 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 AccessExosomal miR-1304-3p promotes breast cancer progression in African Americans by activating cancer-associated adipocytes
The molecular mechanisms explaining racial disparity in breast cancer mortality are not completely elucidated. Here, the authors show that an African-associated SNP in American breast cancer patients, leads to higher levels of microRNA miR-1304-3p which promotes cancer by increasing lipids availability.
- Dan Zhao
- , Kerui Wu
- & Kounosuke Watabe
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Article
| Open AccessA multi-phenotype analysis reveals 19 susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common skin cancers and have genetic overlap. Here, the authors use a multi-trait genetic and phenotypic analysis to reveal susceptibility loci for BCC and SCC, and report an optimised polygenic risk score for risk stratification.
- Mathias Seviiri
- , Matthew H. Law
- & Stuart MacGregor
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Article
| Open AccessExtensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG
The role of risk loci identified from genome-wide association studies in prostate cancer (PCa) progression remains poorly characterised. Here, the authors report enrichment of transcription factor genes within PCa risk-associated regions and germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations.
- Nikolaos Giannareas
- , Qin Zhang
- & Gong-Hong Wei
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Article
| Open AccessReversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies
Mutations in BRCA1/2 are associated with a homologous recombination deficiency phenotype in BRCA-associated cancers. Reversion mutations can restore BRCA1/2 function and result in treatment resistance in these cancer-types. Here, the authors show that, in select cases, reversion mutations in BRCA1/2 can indicate prior BRCA-mediated tumorigenesis in non-canonical histologies.
- Yonina R. Murciano-Goroff
- , Alison M. Schram
- & Alexander Drilon
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Article
| Open AccessRegulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability
The ETV6-RUNX1 chimeric- and native RUNX1-responsive regulomes in paediatric B-acute lymphoblastic leukemia (B-ALL) remain to be characterized. Here, the authors reveal functional antagonism between the two transcription factors predominantly for the regulation of cell cycle-associated pathways and dependency on native RUNX1 for tumorigenesis which can be targeted pharmacologically.
- Jason P. Wray
- , Elitza M. Deltcheva
- & Tariq Enver
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Article
| Open AccessIntegrating transcription factor occupancy with transcriptome-wide association analysis identifies susceptibility genes in human cancers
Transcriptome-wide association studies can uncover genes involved in disease. Here, the authors extend the framework with a transcriptome-wide association study approach which incorporates transcription factor occupancy, adding tissue-specific mechanistic support to associations.
- Jingni He
- , Wanqing Wen
- & Xingyi Guo
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Article
| Open AccessmTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters
Chemotherapy resistance poses a major obstacle in cancer therapy. Here, the authors identify the mTOR pathway as a determinant of chemosensitivity and demonstrate that inhibition of mTOR promotes the persistence of a chemotherapy-resistant cancer-cell subpopulation.
- Yuanhui Liu
- , Nancy G. Azizian
- & Yulin Li
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Article
| Open AccessReplication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells
Suppression of transcription in S-phase is crucial to prevent genome instability. Zhang et al demonstrate that increase of H4K20me1 due to loss of Kmt5b cause genome instability in muscle stem cells, resulting in stem cell senescence but rhabdomyosarcoma formation when p53 is inactivated.
- Ting Zhang
- , Carsten Künne
- & Thomas Braun
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Article
| Open AccessSister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51
Sister chromatid exchanges (SCEs) are considered to be products of homologous recombination repair. The authors show that SCEs can arise independently of homologous recombination due to processing of replication intermediates during mitosis.
- Anne Margriet Heijink
- , Colin Stok
- & Marcel A. T. M. van Vugt
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Article
| Open AccessAnalysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers
Carriers of pathogenic BRCA1/2 variants have a higher risk of breast and ovarian cancers, which recur frequently. Here, the authors sequence primary and recurrent tumours of BRCA1/2 mutation carriers, finding PARP1 amplifications, differential BRCA2 isoform usage, and discordant loss of heterozygosity that are associated with recurrence.
- Jennifer B. Shah
- , Dana Pueschl
- & Katherine L. Nathanson
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Article
| Open AccessMIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia
The links between DNA methylation and gene expression are poorly understood on large-scale. Here the authors show that MIR retrotransposons within introns can play this role in acute myeloid leukemia harbouring mutations in epigenetic modifiers.
- Aristeidis G. Telonis
- , Qin Yang
- & Maria E. Figueroa
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Article
| Open AccessViral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape
NOTCH mutations are frequent in B cell malignancies. Here the authors use retroviral transduction of primary malignant B cells from Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) patients to show that NOTCH1/2-mutations facilitate mechanism of immune escape.
- Maurizio Mangolini
- , Alba Maiques-Diaz
- & Ingo Ringshausen
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Comment
| Open AccessFunctional genomics of complex cancer genomes
Cancer functional genomics is the study of how genetic, epigenetic, and transcriptional alterations affect cancer phenotypes, such as growth and therapeutic response. Here, we comment on how, taking advantage of next generation sequencing, functional genomics, often combined with systems biology approaches, has revealed novel cancer vulnerabilities beyond the original paradigm of one gene-one phenotype.
- Francesca Menghi
- & Edison T. Liu
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Article
| Open AccessThe comparison of cancer gene mutation frequencies in Chinese and U.S. patient populations
Frequency of cancer-related gene mutations can vary between populations. Here, the authors show differences in TP53 and other gene mutations between the U.S. and Chinese patients, and analyse differences in environmental risk factors to demonstrate that population-specific factors should be considered when discussing cancer risk.
- Fayang Ma
- , Kyle Laster
- & Zigang Dong
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Article
| Open AccessHigh-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance
Multiple alternative splicing events in CD19 mRNA have been associated with resistance/relapse to CD19 CAR-T therapy in patients with B cell malignancies. Here, by combining patient data and a high-throughput mutagenesis screen, the authors identify single point mutations and RNA-binding proteins that can control CD19 splicing and be associated with CD19 CAR-T therapy resistance.
- Mariela Cortés-López
- , Laura Schulz
- & Julian König
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Article
| Open AccessConserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer
TERT promoter mutations are the most common noncoding alterations in cancers, although some remain to be characterised. Here, the authors identify TERT promoter duplications across seven cancer types that are functionally equivalent to well-known hotspot TERT mutations and are clonal in a multifocal glioblastoma patient.
- Carter J. Barger
- , Abigail K. Suwala
- & Joseph F. Costello
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Article
| Open AccessPangenomic analysis of Chinese gastric cancer
Human pan-genomics are increasing our knowledge of genomic diversity and genetic factors in disease. Here, the authors built a gastric cancer pan-genome that included the sequences of Chinese Han patients, and predicted putative and previously unaligned genes associated with gastric cancer.
- Yingyan Yu
- , Zhen Zhang
- & Zhenggang Zhu
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Article
| Open AccessGermline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis
Myelofibrosis is a risk factor for the development of Acute Myeloid Leukaemia. Here, the authors carry out an integrated genomic investigation of 933 myelofibrosis patients, and identified interactions between germline and somatic variation in patients who required haematopoietic cell transplantation.
- Derek W. Brown
- , Weiyin Zhou
- & Mitchell J. Machiela
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Article
| Open AccessA common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors
Intracranial germ cell tumors (IGCTs) are rare brain tumors mainly diagnosed in children and young adults. Here, the authors conduct a genome-wide association study for IGCTs, identify a risk locus at BAK1, and characterize its functional consequences.
- Kyuto Sonehara
- , Yui Kimura
- & Keita Terashima
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Article
| Open AccessComprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity
The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.
- Lino Möhrmann
- , Maximilian Werner
- & Hanno Glimm
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Article
| Open AccessDNA nicks induce mutational signatures associated with BRCA1 deficiency
It remains unclear how BRCA1-associated mutational sigantures are generated in cancer. Here, the authors develop nCas9-based approaches to uncover that aberrant repair of one-ended DSBs converted from DNA nicks by replication, not that of two-ended DSBs, induces such mutational signatures.
- Yi-Li Feng
- , Qian Liu
- & An-Yong Xie
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Article
| Open AccessCutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure
While cutaneous melanoma is linked to UV radiation, acral melanoma is not. Epigenetic mechanisms function as sensors to exposures and determinants of cell identity. Here, the authors use DNA methylation data to identify dysregulated pathways associated with UV radiation and pathobiology in cutaneous and acral melanomas.
- Anna Luiza Silva Almeida Vicente
- , Alexei Novoloaca
- & Akram Ghantous
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Article
| Open AccessUltra-sensitive monitoring of leukemia patients using superRCA mutation detection assays
Rare tumour specific mutations in patient samples act as markers to monitor the course of disease. Here the authors report superRCA assays for rapid, highly specific detection of DNA sequence variants present at very low frequencies in DNA samples with flow cytometry readout; they use this on AML patients.
- Lei Chen
- , Anna Eriksson
- & Ulf Landegren
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Article
| Open AccessRecurrent somatic mutations as predictors of immunotherapy response
Few genetic biomarkers are known for cancer immunotherapy. Here the authors identify recurrently-mutated genes and pathways associated with treatment response and develop a classifier using tumour whole exome sequencing and clinical features.
- Zoran Z. Gajic
- , Aditya Deshpande
- & Neville E. Sanjana
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Article
| Open AccessInherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
Inherited mutations in MUTYH have been shown to predispose patients to colorectal cancers. Here, the authors show that MUTYH mutations lead to an increased somatic base substitution mutation rate in normal intestinal epithelial cells, which is the likely cause for the increased cancer risk.
- Philip S. Robinson
- , Laura E. Thomas
- & Michael R. Stratton
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Article
| Open AccessClinical relevance of molecular characteristics in Burkitt lymphoma differs according to age
Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.
- Birgit Burkhardt
- , Ulf Michgehl
- & Georg Lenz
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Article
| Open AccessThe genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma
The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.
- Josh N. Vo
- , Yi-Mi Wu
- & Arul M. Chinnaiyan
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Article
| Open AccessThe impact of rare germline variants on human somatic mutation processes
The impact of germline variants on somatic alterations in cancer remains to be explored in large-scale datasets. Here, the authors study the association of rare germline variants with somatic mutational processes in more than 15,000 tumors, and reveal that damaging variants in newly-identifed genes are prevalent in the population.
- Mischan Vali-Pour
- , Solip Park
- & Fran Supek
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Article
| Open AccessARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription
Here the authors show mutation of the BAF chromatin remodeler subunit ARID1A results in an ARID1B-dependent upregulation of HERVH, an ERV required for the pluripotency regulatory network. These HERVH RNAs can partition into BRD4 foci, affecting BRD4-dependent transcription. Suppression of HERVH in colorectal cancer cells and patient-derived organoids impairs tumor growth.
- Chunhong Yu
- , Xiaoyun Lei
- & Kai Yuan
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Article
| Open AccessPhasing analysis of lung cancer genomes using a long read sequencer
Long-read sequencing technologies are useful for the multifaceted task of characterising somatic mutations, including structural variants, in cancers. Here, the authors combine short and long read sequencing for the phasing analysis, which enables them to resolve the chromosomal backgrounds of somatic mutations in Japanese non-small cell lung cancers.
- Yoshitaka Sakamoto
- , Shuhei Miyake
- & Ayako Suzuki