Featured
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| Open AccessMolecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma
Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.
- Fabian Frontzek
- , Annette M. Staiger
- & Georg Lenz
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Article
| Open AccessRNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage
The BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex is well known to play a fundamental role in DNA repair, but how the complex recruitment is regulated is still a matter of interest. Here the authors reveal mechanistic insights into RNF168 activity being responsible for PALB2 recruitment, through BARD1-BRCA1 during homologous recombination repair.
- John J. Krais
- , Yifan Wang
- & Neil Johnson
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Article
| Open AccessChronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma
Characterising the clonal architecture of Adult T-cell leukemia-lymphoma (ATL) remains crucial. Here, the authors develop a capture-based sequencing panel and use deep DNA and single cell RNA sequencing and report distinct genomic and transcriptomic features associated with subclonal evolution.
- Makoto Yamagishi
- , Miyuki Kubokawa
- & Kaoru Uchimaru
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Article
| Open AccessIdentification of 22 susceptibility loci associated with testicular germ cell tumors
Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.
- John Pluta
- , Louise C. Pyle
- & Christian Kubisch
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Article
| Open AccessOncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis
The role of regulatory cis-elements in carcinogenesis and metastasis in esophageal squamous cell carcinoma remains crucial. Here the authors investigate H3K27ac-marked active enhancer profiles and transcriptomes in different types of esophageal tissues and identify oncogenic events and potential therapeutic targets.
- Bo Ye
- , Dandan Fan
- & Yunbo Qiao
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Article
| Open AccessInterplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer
The relevance and underlying molecular mechanisms of epigenetic regulation in squamous cell carcinomas (SCC) await further characterization. Here, the authors show a transcriptional regulatory loop involving SREBF1, TP63 and KLF5 driving tumourigenesis in SCC through fatty acid, ERBB and mTOR pathway regulation.
- Li-Yan Li
- , Qian Yang
- & De-Chen Lin
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Article
| Open AccessTargeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
Kras is frequently mutated in lung cancer and two isoforms are generated via alternative splicing. Here, the authors show that the two isoforms have divergent roles in cancer stem cells and the main tumour cell population, which are regulated by hypoxia and endoplasmic reticulum stress.
- Wei-Ching Chen
- , Minh D. To
- & Allan Balmain
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Article
| Open AccessOncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia
SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.
- Quentin Van Thillo
- , Jolien De Bie
- & Charles E. de Bock
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Article
| Open AccessHigh-resolution characterization of gene function using single-cell CRISPR tiling screen
Identifying functional domains and genetic regulatory mechanisms is essential for developing new therapies. Here the authors present sc-Tiling, single-cell high-density CRISPR tiling screening for functional domain characterization.
- Lu Yang
- , Anthony K. N. Chan
- & Chun-Wei Chen
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Article
| Open AccessFusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified
Peripheral T cell lymphoma (PTCL) not otherwise specified (NOS) is a subgroup of PTCL, which has no distinctive features and is poorly characterized at the genetic level. Here, the authors identify two fusion transcripts that activate T cell receptor complex signalling and confer therapeutic vulnerability in PTCL-NOS.
- Koen Debackere
- , Lukas Marcelis
- & Daan Dierickx
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Article
| Open Access3D genome alterations associated with dysregulated HOXA13 expression in high-risk T-lineage acute lymphoblastic leukemia
The non-coding genome of T-ALL has not been extensively studied. Here, the authors conduct RNA-seq, ATAC-seq and Hi-C seq analyses and find that T-ALL associated neo-loops may regulate key transcription factors including HOXA13; the aberrant expression of which is associated with poor prognosis.
- Lu Yang
- , Fengling Chen
- & Hong Wu
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Comment
| Open AccessHoming in on genomic instability as a therapeutic target in cancer
While genomic instability is a hallmark of cancer, its genetic vulnerabilities remain poorly understood. Identifying strategies that exploit genomic instability to selectively target cancer cells is a central challenge in cancer biology with major implications for anti-cancer drug development.
- Craig M. Bielski
- & Barry S. Taylor
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Article
| Open AccessGenetic variation associated with thyroid autoimmunity shapes the systemic immune response to PD-1 checkpoint blockade
Endocrinopathies, such as thyroid autoimmunity, are common among patients treated with immune checkpoint inhibitors. Here, by using a polygenic risk score (PRS) derived from a hypothyroidism GWAS, the authors show that cancer patients with high PRS are at increased risk of atezolizumab (anti-PD-L1)-induced thyroid dysfunction, a condition associated with systemic response to PD-1 checkpoint blockade and longer overall survival.
- Zia Khan
- , Christian Hammer
- & G. Scott Chandler
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Article
| Open AccessClonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia
In chronic myeloid leukaemia (CML), the drivers of blast crisis and resistance to tyrosine kinase inhibitors are not fully characterised. Here, the authors analyse a cohort of CML samples with genomic technologies and find that at least one driver alteration is associated with progression and worse prognosis.
- Yotaro Ochi
- , Kenichi Yoshida
- & Lee-Yung Shih
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Article
| Open AccessLeukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance.
- Feng Wang
- , Kiyomi Morita
- & Koichi Takahashi
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Article
| Open AccessA clinical transcriptome approach to patient stratification and therapy selection in acute myeloid leukemia
Several genomic features have been found for acute myeloid leukaemia (AML) but targeted clinical genetic testing fails to predict prognosis. Here, the authors generate an AML prognostic score from RNA-seq data of patients, which successfully stratifies AML patients and which may provide guidance for therapeutic strategies.
- T. Roderick Docking
- , Jeremy D. K. Parker
- & Aly Karsan
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Article
| Open AccessGenomic profile of advanced breast cancer in circulating tumour DNA
Circulating tumour DNA can provide useful information on disease burden. Here, the authors analysed circulating tumour DNA from 800 patients from a breast cancer clinical trial and investigate the subclonal nature of the disease, and identify DNA mutations associated with resistance and poor survival.
- Belinda Kingston
- , Rosalind J. Cutts
- & Nicholas C. Turner
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Article
| Open AccessArginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells
Alterations in metabolism and amino acid usage are common in cancer cells. Here, the authors show in prostate cancer cells that arginine globally upregulates nuclear-encoded oxidative phosphorylation genes by altering histone acetylation and retaining TEAD4 in the nucleus to transactivate genes.
- Chia-Lin Chen
- , Sheng-Chieh Hsu
- & Hsing-Jien Kung
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Article
| Open AccessRAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways
RAC1 is a downstream target of the Wnt signaling that promotes intestinal stem cell expansion and tumorigenesis. Here, the authors identify the specific splice variant RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment.
- Victoria Gudiño
- , Sebastian Öther-Gee Pohl
- & Kevin B. Myant
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Article
| Open AccessImproved prime editors enable pathogenic allele correction and cancer modelling in adult mice
Prime editors use a template sequence within their pegRNA to facilitate nucleotide substitutions or local indels. Here the authors use AAVs to deliver a split-intein prime editor in vivo to correct a pathogenic mutation.
- Pengpeng Liu
- , Shun-Qing Liang
- & Wen Xue
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Article
| Open AccessThe origins and genetic interactions of KRAS mutations are allele- and tissue-specific
The KRAS gene is often mutated at several hotspot codons in cancer, resulting in similar, yet distinct, functional impacts on the KRAS protein. Here, the authors examine the genetic interactions of the different KRAS mutations across multiple cancer types and discover that KRAS mutations have allele- and tissue-specific mutagenic origins, comutation patterns, and dependency interactions.
- Joshua H. Cook
- , Giorgio E. M. Melloni
- & Kevin M. Haigis
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Article
| Open AccessCRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer
Prostate cancer risk-associated SNPs are enriched in noncoding CREs. Here the authors perform CRISPRi screens of CREs in prostate cancer cell lines to describe a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture.
- Musaddeque Ahmed
- , Fraser Soares
- & Housheng Hansen He
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Matters Arising
| Open AccessFormal reply to “Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX”
- Lars Feuerbach
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Matters Arising
| Open AccessAlternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX
- Alexandre de Nonneville
- & Roger R. Reddel
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Article
| Open AccessRetroviral integrations contribute to elevated host cancer rates during germline invasion
Koalas are susceptible to neoplasms, which are related to infection with the Koala retrovirus. Here, the authors use DNA sequencing to show that the retroviral insertion sites cluster near known cancer genes and demonstrate a high mutational load associated with the germline invasion of the virus.
- Gayle K. McEwen
- , David E. Alquezar-Planas
- & Alex D. Greenwood
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Article
| Open AccessA case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
- Juliette Coignard
- , Michael Lush
- & Antonis C. Antoniou
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Article
| Open AccessZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism
The fusion gene ZMYND11-MBTD1 (ZM) is present in a subgroup of patients with acute myeloid leukaemia (AML). Here, the authors show that ZM expression induces AML in a murine model though activating the NuA4/TIP60 histone acetyltransferase complex.
- Jie Li
- , Phillip M. Galbo Jr.
- & Gang Greg Wang
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Article
| Open AccessCross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts
While genetic loci shared between cancer types have been identified, cross-cancer relationships for polygenic risk scores have not been well studied. Here, the authors have developed polygenic risk scores for 16 cancers in two large cohorts and identified positive and inverse cross-cancer associations.
- Rebecca E. Graff
- , Taylor B. Cavazos
- & Lori C. Sakoda
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Article
| Open AccessDual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer
Gene fusions involving the ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are two truncal mutations that are mutually exclusively present in prostate cancer. Here, the authors show that mutations in SPOP render prostate tumor cells sensitive to antiandrogen therapy and that the presence of ERG promotes sensitivity to high dose of androgen and SPOP inhibition.
- Tiziano Bernasocchi
- , Geniver El Tekle
- & Jean-Philippe P. Theurillat
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Article
| Open AccessPretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors
There is an unmet clinical need for simple, accessible biomarkers to select patients who are more likely to respond to immune checkpoint therapy. Here the authors show that a lower neutrophil-to-lymphocyte ratio is associated with better overall and progressive-free survival, as well as higher rate of response, in a multi-cancer cohort of patients treated with immune checkpoint inhibitors.
- Cristina Valero
- , Mark Lee
- & Luc G. T. Morris
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Article
| Open AccessDe novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands
Aberrant gain of DNA methylation at CpG islands is frequently observed in colorectal tumours. Here the authors use ectopically integrated CpG islands in colorectal cancer cells and find that aberrantly methylated CpG islands are subject to low levels of de novo DNA methylation, and that instead de novo DNA methylation activity is targeted primarily to CpG islands marked by the histone modification H3K36me3.
- Roza H. Ali Masalmeh
- , Francesca Taglini
- & Duncan Sproul
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Article
| Open AccessGenome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia
The clinical course of chronic lymphocytic leukaemia (CLL) is variable and difficult to predict. Here, the authors conduct a genome wide association study meta-analysis for time to first treatment in CLL patients and report two loci associating with progressive disease.
- Wei-Yu Lin
- , Sarah E. Fordham
- & James M. Allan
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Article
| Open AccessOncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres
~15% of cancers induce alternative lengthening of telomeres (ALT) to activate telomere maintenance. Here, the authors reveal that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces acquisition of ALT-like features in previously non-ALT cell lines.
- Timothy P. Lippert
- , Paulina Marzec
- & Simon J. Boulton
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Article
| Open AccessShort H2A histone variants are expressed in cancer
Short H2A variants are testis-specific histones that destabilize nucleosomes during spermatogenesis. In this study, the authors show that these variants are expressed in an array of different cancers and identify splicing changes associated with nucleosome instability in these malignancies.
- Guo-Liang Chew
- , Marie Bleakley
- & Jay Sarthy
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Article
| Open AccessA comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization
Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.
- Jue-Sheng Ong
- , Suzanne C. Dixon-Suen
- & Stuart MacGregor
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Article
| Open AccessThe role of polygenic risk and susceptibility genes in breast cancer over the course of life
Identifying women at high risk of breast cancer has important implications for screening. Here, the authors demonstrate that polygenic risk scores improve breast cancer risk prediction in the population, in women with mutations in high-risk genes and in women with close relatives with the disease.
- Nina Mars
- , Elisabeth Widén
- & Samuli Ripatti
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Article
| Open AccessPan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction
Predicting cancer risk requires large datasets and sophisticated models. Here the authors integrate polygenic risk scores and modifiable risk factors for multiple cancers in the UK Biobank, improving general risk prediction and distinguishing cases where genetic or lifestyle factors have stronger associations.
- Linda Kachuri
- , Rebecca E. Graff
- & Mattias Johansson
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Article
| Open AccessQuantitative and multiplexed chemical-genetic phenotyping in mammalian cells with QMAP-Seq
Identifying chemical-genetic interactions in mammalian cells is limited to low-throughput or computational methods. Here, the authors present QMAP-Seq, a broadly accessible and scalable approach that uses NGS for pooled high-throughput chemical-genetic profiling in mammalian cells.
- Sonia Brockway
- , Geng Wang
- & Marc L. Mendillo
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Article
| Open AccessThe tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition
Human Long INterspersed Element class 1 (LINE-1) elements are expressed and mobilized in many types of cancer, contributing to malignancy. Here the authors show that the tumor suppressor microRNA let-7 targets the LINE-1 mRNA and reduces LINE-1 mobilization.
- Pablo Tristán-Ramos
- , Alejandro Rubio-Roldan
- & Sara R. Heras
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Article
| Open AccessCharacterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing
Chinese breast cancer patients have not been well represented in clinical sequencing studies. Here the authors analyse the mutational landscape of 1,134 Chinese breast cancer patients, finding actionable targets and a higher prevalence of p53 and Hippo pathway mutations compared to Western cohorts.
- Guan-Tian Lang
- , Yi-Zhou Jiang
- & Zhi-Ming Shao
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Article
| Open AccessDiscovery of driver non-coding splice-site-creating mutations in cancer
Non-coding cancer driver mutations that induce splicing variants exist, but are largely unexplored. Here, the authors find these non-coding mutations in known pan-cancer driver genes and show that they create new exons and might interact with pre-existing potential splice sites.
- Song Cao
- , Daniel Cui Zhou
- & Li Ding
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Article
| Open AccessRole of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity
The differentiation of prostate adenocarcinoma to neuroendocrine prostate cancer (CRPC-NE) is a mechanism of resistance to androgen deprivation therapy. Here the authors show that SWI/SNF chromatin-remodeling complex is deregulated in CRPC-NE and that the complex interacts with different lineage specific factors throughout prostate cancer transdifferentiation.
- Joanna Cyrta
- , Anke Augspach
- & Mark A. Rubin
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Article
| Open AccessThe HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s
The HUSH complex has been implicated in repressing LINE-1 elements. Here the authors reveal that the complex negatively regulates the type I IFN response in human cells through epigenetic regulation of LINE-1 elements
- Hale Tunbak
- , Rocio Enriquez-Gasca
- & Helen M. Rowe
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Article
| Open AccessCirculating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma
Non-invasive and precise methods are critical for monitoring paediatric brain cancers. Here the authors show that the molecular alterations and heterogeneity of paediatric medulloblastomas can be reliably detected in circulating tumour DNA from the cerebrospinal fluid – a routinely collected sample.
- Laura Escudero
- , Anna Llort
- & Joan Seoane
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Article
| Open AccessPan-neuroblastoma analysis reveals age- and signature-associated driver alterations
Genomic analysis of neuroblastoma has revealed important disease etiology. In this study, the authors assembled whole genome, exome and transcriptome data from over 700 neuroblastomas and identified molecular signatures correlated with age, and rare, potentially targetable variants overlooked in smaller cohorts.
- Samuel W. Brady
- , Yanling Liu
- & Jinghui Zhang
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Article
| Open AccessMultiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma
Meningiomas are heterogeneous tumours. Here, the authors analysed genetic, epigenetic, and transcriptomic features across spatially-distinct meningioma samples to identify molecular programs underlying tumorigenesis that can be detected preoperatively using magnetic resonance imaging.
- Stephen T. Magill
- , Harish N. Vasudevan
- & David R. Raleigh
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Article
| Open AccessTelomere dysfunction activates YAP1 to drive tissue inflammation
How telomere dysfunction is directly linked to inflammation in humans is currently unclear. Here the authors reveal that telomere dysfunction drives activation of the YAP1 transcription factor, up-regulating the pro inflammatory factor, pro-IL-18 thus revealing a link between telomere dysfunction and initiation of intestinal inflammation.
- Deepavali Chakravarti
- , Baoli Hu
- & Ronald A. DePinho
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Article
| Open AccessA phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
RNF43 is frequently mutated in cancers and negatively regulates Wnt signalling. Here, the authors report that RNF43 phosphorylation at a serine triplet is required for the negative regulation of Wnt signalling and that the phosphorylation of RNF43 suppresses cancer-associated oncogenic RNF43 mutants.
- Tadasuke Tsukiyama
- , Juqi Zou
- & Shigetsugu Hatakeyama
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Article
| Open AccessPan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts
Pleiotropic loci and genome-wide genetic correlations have identified shared heritability across some types of cancers. Here, the authors perform genome-wide association studies and characterize pan-cancer heritability and pleiotropy in individuals of European ancestry across 18 cancer types from two large cohorts.
- Sara R. Rashkin
- , Rebecca E. Graff
- & John S. Witte