Featured
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| Open AccessPostpartum breast cancer has a distinct molecular profile that predicts poor outcomes
The molecular differences between postpartum (PPBC) and nulliparous (NPBC) young women breast cancer (YWBC) patients remain unknown. Here the authors perform RNA sequencing and multiplex immunohistochemistry on an FFPE breast cancer cohort and suggest that PPBC is a unique entity within YWBC with poor prognosis.
- Sonali Jindal
- , Nathan D. Pennock
- & Pepper Schedin
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Article
| Open AccessLongitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression
The molecular programs that underlie progression in multiple myeloma (MM) are incompletely understood. Here the authors use a mouse model of MM and single-cell RNA-seq to define subclonal expression programs that arise during progression and that inform targeted therapeutic strategies.
- Danielle C. Croucher
- , Laura M. Richards
- & Suzanne Trudel
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Article
| Open AccessInhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
Mutations in histone acetyltransferases (HATs) CREBBP and EP300 are generally thought to lead to decreased function or absence of protein product. Here the authors describe a gain of function of several CREBBP mutations leading to baseline hyper-acetylation, increased homologous recombination and potential synergy between radiation and HAT inhibition in CREBBP/EP300 mutant tumors.
- Manish Kumar
- , David Molkentine
- & Heath D. Skinner
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Article
| Open AccessMulti-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes
Triple negative breast cancer can be divided into additional subtypes. Here, using omics analyses, the authors show that in the mesenchymal subtype expression of MHC-1 is repressed and that this can be restored by using drugs that target subunits of the epigenetic modifier PRC2.
- Brian D. Lehmann
- , Antonio Colaprico
- & X. Steven Chen
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Article
| Open AccessSomatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
Biomarkers of prostate cancer metastasis have been difficult to determine with confidence. Here the authors analyse mutation prevalence in 1844 prostate cancers and show that ZNRF3 loss is enriched in metastatic, castration-resistant prostate cancer and associated with metastasis of localized disease.
- Michael Fraser
- , Julie Livingstone
- & Paul C. Boutros
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Article
| Open AccessGenome-wide association study identifies susceptibility loci for acute myeloid leukemia
Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.
- Wei-Yu Lin
- , Sarah E. Fordham
- & James M. Allan
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Article
| Open AccessSingle-cell transcriptomic analysis of the tumor ecosystems underlying initiation and progression of papillary thyroid carcinoma
The characterisation of the papillary thyroid carcinoma (PTC) tumour microenvironment remains crucial. Here, the authors perform single-cell RNA sequencing in 11 patients and identify potential opportunities for the use of immunotherapy and its combination with anti-angiogenic therapy in PTC.
- Weilin Pu
- , Xiao Shi
- & Yu-Long Wang
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Article
| Open AccessSingle cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy
The response rate of relapsed/refractory acute myeloid leukemia patients to PD-1 checkpoint blockade is low and unpredictable. Authors here show by single cell RNA sequencing, T cell receptor profiling and genomic analysis that the phenotypes and repertoire of CD8 + T cells and loss of chromosome 7/7q are important determinants of response.
- Hussein A. Abbas
- , Dapeng Hao
- & Andrew Futreal
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Article
| Open AccessCancer gene mutation frequencies for the U.S. population
Understanding the frequency of gene mutations in cancer could be important for generating targeted therapeutics. Here, the authors use SEER data and cancer genomics data from TCGA to estimate the gene mutation frequencies in the US cancer population.
- Gaurav Mendiratta
- , Eugene Ke
- & Edward C. Stites
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Article
| Open AccessSingle-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy
Pancreatic tumors are frequently divided into basal and classical subtypes. Here, the authors use single cell sequencing to investigate organoids derived from pancreatic cancer tissue and find a hierarchy of distinct cell states, and classical and basal cells existing within the same tumor.
- Teresa G. Krieger
- , Solange Le Blanc
- & Christian Conrad
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Article
| Open AccessDeterminants of renal cell carcinoma invasion and metastatic competence
Tumour thrombi (TT) are intravascular extensions of renal cell carcinomas (RCC) which often lead to distant metastases. Here the authors examine the determinants of vascular invasion and metastasis in a unique cohort of RCC patients with TT using multi-region genomics and in vivo models.
- Kangsan Kim
- , Qinbo Zhou
- & Srinivas Malladi
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Article
| Open AccessSubtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer
Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.
- Paloma Cejas
- , Yingtian Xie
- & Henry W. Long
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Article
| Open AccessChromatin accessibility associates with protein-RNA correlation in human cancer
Studies show the cancer transcriptome correlates poorly with the cancer proteome, questioning the role of chromatin regulation. Here the authors demonstrate proximal-gene-body chromatin elements and transcription predict abundances of differentially expressed proteins in thyroid and breast cancers.
- Akshay Sanghi
- , Joshua J. Gruber
- & Michael P. Snyder
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Article
| Open AccessSystems approaches identify the consequences of monosomy in somatic human cells
The mechanisms that allow cancer cells to survive with monosomies are poorly understood. Here the authors analyse p53-deficient monosomic cell lines using transcriptomics and proteomics, and find that impaired ribosome biogenesis and p53 downregulation are associated with sustained monosomies.
- Narendra Kumar Chunduri
- , Paul Menges
- & Zuzana Storchova
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Article
| Open AccessSON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
Splicing factor PTBP1 is reported to promote oncogenic functions in glioblastoma (GBM). Here the authors show splicing factor SON upregulates PTBP1 expression while supresses its paralog PTBP2 through alternative splicing and the inhibition of SON reduces GBM stemness and growth.
- Jung-Hyun Kim
- , Kyuho Jeong
- & Eun-Young Erin Ahn
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Article
| Open AccessRadiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B
Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies but their origin are still unclear. Here, the authors define the genomic, epigenetic and transcriptional landscape of 32 RIGs cases.
- Maximilian Y. Deng
- , Dominik Sturm
- & David T. W. Jones
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Article
| Open AccessGenetic and epigenetic basis of hepatoblastoma diversity
While hepatoblastoma is the most common pediatric liver cancer, its molecular background has not been fully characterised. Here, the authors perform genomic and epigenomic profiling of 163 untreated pediatric liver tumours and suggest the upregulation of ASCL2 and methylation patterns of IGF2 promoters in driving hepatoblast carcinogenesis.
- Genta Nagae
- , Shogo Yamamoto
- & Eiso Hiyama
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Article
| Open AccessComprehensive molecular characterization of pediatric radiation-induced high-grade glioma
Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. In the largest study to date, we report the results of DNA methylation profiling, RNA-Seq and genomic sequencing of 32 RIG tumors, and an in vitro drug screen in two RIG cell lines.
- John DeSisto
- , John T. Lucas Jr.
- & Adam L. Green
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Comment
| Open AccessBreaking down walls in prostate cancer with the MURAL collection of patient-derived xenografts
A bank of 59 well-characterised prostate cancer patient-derived xenografts was established, including 17 classed as research-ready covering the disease-spectrum which, plus associated resources (organoids, serum, DNA/RNA profiles, tissue), are available for collaborative projects. This eagerly-anticipated resource will facilitate pre-clinical prostate cancer therapy studies.
- Charlotte L. Bevan
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Article
| Open AccessA human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery
Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.
- Emilie Crouchet
- , Simonetta Bandiera
- & Thomas F. Baumert
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Article
| Open AccessMulti-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer
Multi-region sequencing of small cell lung cancers (SCLC) can improve our understanding of the disease. Here the authors analyse 120 multi-region samples from 40 SCLC patients with whole exome sequencing and characterise their mutational burden, evolution, heterogeneity, and potential prognostic biomarkers.
- Huaqiang Zhou
- , Yi Hu
- & Ningning Zhou
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Article
| Open AccessParity associates with chromosomal damage in uterine leiomyomas
Many factors have been associated with chromosomal damage, including mechanical forces in a constrained cellular environment. Here the authors reveal an association between parity and chromosomal damage by analysing karyotypes of 1946 uterine leiomyomas.
- Heli Kuisma
- , Simona Bramante
- & Lauri A. Aaltonen
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Article
| Open AccessMulti-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia
Chronic lymphocytic leukemia has been studied using multiple levels of omics data. Here, the authors use exome sequencing, SNP, protein and gene expression data to identify distinct biologic tumor subtypes with heterogeneous prognostic impact after chemo- or immunochemotherapy.
- Johannes Bloehdorn
- , Andrejs Braun
- & Daniel Mertens
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Article
| Open AccessCloneSig can jointly infer intra-tumor heterogeneity and mutational signature activity in bulk tumor sequencing data
Intratumour heterogeneity (ITH) and mutational signatures are typically analysed separately, even though they are not necessarily independent. Here, the authors present CloneSig, a tool for the joint estimation of ITH and mutational signatures, with which they analyse the TCGA and PCAWG datasets.
- Judith Abécassis
- , Fabien Reyal
- & Jean-Philippe Vert
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Article
| Open AccessIntegrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma
TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare subtype of kidney cancer with no standard treatment options for the advanced disease. Here, the authors perform genomic and transcriptomic profiling of 63 untreated primary TFE3-tRCC tumours and reveal potential therapeutic targets.
- Guangxi Sun
- , Junru Chen
- & Hao Zeng
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Article
| Open AccessSingle allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer
Transposon based screens carried out in mice can identify genes critical for tumourigensis. Here, the authors describe transposon screens in mouse models of breast cancer and highlight a large group of tumour suppressors that could underlie selection for common chromosome arm losses in cancer.
- Nathan F. Schachter
- , Jessica R. Adams
- & Sean E. Egan
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Article
| Open AccessThe PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma
The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma. Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival.
- Lars Ny
- , Henrik Jespersen
- & Jonas A. Nilsson
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Article
| Open AccessPan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity
Although circulating tumour DNA (ctDNA) can predict immune checkpoint blockade (ICB) responses, its association with tumour biomarkers remains unknown. Here, the authors use ctDNA to inform exome and transcriptome profiling of >100 patients with 30 cancer types on a single clinical ICB trial and identify tumour microenvironment features associated with response.
- S. Y. Cindy Yang
- , Scott C. Lien
- & Trevor J. Pugh
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Article
| Open AccessComprehensive characterization of 536 patient-derived xenograft models prioritizes candidates for targeted treatment
Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.
- Hua Sun
- , Song Cao
- & Li Ding
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Article
| Open AccessThe MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology
The prognosis of castration-resistant prostate cancers remains dismal, but accurate preclinical models can lead to effective therapies. Here the Melbourne Urological Research Alliance establish prostate cancer patient-derived xenografts, use the tumors for organoids and single-cell RNA-seq, and show the efficacy of PARP inhibitor combination treatments.
- Gail P. Risbridger
- , Ashlee K. Clark
- & Renea A. Taylor
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Matters Arising
| Open AccessReply to: Reconciling differences in impact of molecular subtyping on response to cisplatin-based chemotherapy
- Ann Taber
- , Emil Christensen
- & Lars Dyrskjøt
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Matters Arising
| Open AccessReconciling differences in impact of molecular subtyping on response to cisplatin-based chemotherapy
- Mathieu Roumiguie
- , Alberto Contreras-Sanz
- & Peter C. Black
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Article
| Open AccessPredictive biomarkers for 5-fluorouracil and oxaliplatin-based chemotherapy in gastric cancers via profiling of patient-derived xenografts
Gastric cancer is commonly treated by chemotherapy using 5-fluorouracil derivatives and platinum combination, but predictive biomarker remains lacking. Here, the authors develop a 30-gene prediction model to determine the responsiveness to 5-fluorouracil and oxaliplatin-based chemotherapy through the integrative profiling of patient-derived xenografts
- Deukchae Na
- , Jeesoo Chae
- & Jong-Il Kim
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Article
| Open AccessThe evolution of hematopoietic cells under cancer therapy
The mutational effects of chemotherapies on healthy cells are unclear. Here, the authors show that the mutational signature of platinum-based drugs -but not 5-fluorouracil- is detectable in secondary acute myeloid leukemia, implying that the clonal expansion begins after the start of therapy.
- Oriol Pich
- , Albert Cortes-Bullich
- & Nuria Lopez-Bigas
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Article
| Open AccessGenomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer
The progression from biliary tract intraepithelial neoplasia (BilIN) to gallbladder carcinoma (GBC) remains unclear. Here the authors use genomics to analyze coexisting GBC lesions, low-grade and high-grade BilINs, revealing two distinct evolutionary paths for GBC development.
- Jianzhen Lin
- , Xinxin Peng
- & Han Liang
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Article
| Open AccessCanine tumor mutational burden is correlated with TP53 mutation across tumor types and breeds
Genomic studies of canine tumours have been done for individual cancer types or dog breeds. Here the authors analyse canine tumour genomics data across multiple breeds and cancer types, finding that mutational burden is associated with TP53 mutations and that Golden Retrievers are enriched for particular signatures.
- Burair A. Alsaihati
- , Kun-Lin Ho
- & Shaying Zhao
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Article
| Open AccessThe genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets
Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) display heterogeneous clinical and genetic characteristics. Here, the authors investigate the mutational landscape of 85 aNEN by whole genome sequencing and identify distinct subpopulations, tumour mutational burden patterns, drivers and actionable somatic alterations.
- Job van Riet
- , Harmen J. G. van de Werken
- & Bianca Mostert
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Article
| Open AccessAn integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer
It is hypothesized that there are a number of tumor specific driver genes for metastatic prostate cancer. Here, the authors perform genome-wide CRISPRi screens and integrate these data with metastatic prostate cancer functional and clinical genomics data to show that KIF4A and WDR62 drive aggressive prostate cancer phenotypes.
- Rajdeep Das
- , Martin Sjöström
- & Luke A. Gilbert
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Article
| Open AccessLineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival
Heterogeneity in leiomyosarcomas (LMS) makes treatment of the disease challenging. Here the authors analyze LMS heterogeneity and molecular LMS subtypes using genomics and transcriptomics, finding origins in distinct lineages and associations with survival, in addition to the early emergence of metastatic clones.
- Nathaniel D. Anderson
- , Yael Babichev
- & Adam Shlien
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Article
| Open AccessGlucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer
Glucocorticoids (GC) are reported to block cancer cell proliferation, but the mode of action is unclear. Here the authors show that glucocorticoid receptor activation induces cancer cell dormancy in lung cancer by regulating CDKN1C expression through a distal enhancer, and these dormant cells are addicted to IGF-1R signalling pathway.
- Stefan Prekovic
- , Karianne Schuurman
- & Wilbert Zwart
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Article
| Open AccessWhole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape
The genomic characterisation of nasopharyngeal carcinoma (NPC) remains crucial. Here, the authors perform whole-genome sequencing for 70 NPCs with EBV gene expression, report the somatic alterations and EBV-mediated effects converging on NF-κB activation and immune escape and identify targetable homozygous MTAP deletions.
- Jeff P. Bruce
- , Ka-Fai To
- & Kwok-Wai Lo
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Article
| Open AccessSensitive detection of tumor mutations from blood and its application to immunotherapy prognosis
It is possible to call single-nucleotide variant (SNV) in cell-free DNA (cfDNA), but the accuracy of detection is often affected by low tumour cfDNA content. Here, the authors develop a method, cfSNV, and show that it can be used even for medium-coverage whole exome sequencing of cfDNA.
- Shuo Li
- , Zorawar S. Noor
- & Xianghong Jasmine Zhou
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Article
| Open AccessMolecular determinants of response to PD-L1 blockade across tumor types
PD-L1 immune checkpoint inhibition has been used for several tumour types. Here, the authors use immunohistochemistry, tumour mutation burden and RNA-seq data from 366 patients with different indications to identify molecular signatures of response to atezolizumab and reveal pathway heterogeneity and the involvement of non-immune pathways.
- Romain Banchereau
- , Ning Leng
- & Thomas Powles
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Article
| Open AccessWhole-exome sequencing of alpha-fetoprotein producing gastric carcinoma reveals genomic profile and therapeutic targets
Alpha-fetoprotein producing gastric carcinomas (AFPGC) are rare and aggressive. Here, the authors profile AFPGC tumours using whole exome sequencing, and find amplifications in CCNE1 and ERBB2 that are associated with poor outcomes but are potential therapeutic targets, as shown in patient-derived xenografts.
- Jun Lu
- , Yongfeng Ding
- & Lisong Teng
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Article
| Open AccessSingle cell derived mRNA signals across human kidney tumors
Transcriptomic analysis may provide information about the differentiation state and cell of origin of a cancer. Here, the authors assess mRNA signals in 1300 childhood and adult renal tumors and report a fetal origin of childhood tumors and no dedifferentiation of adult tumors.
- Matthew D. Young
- , Thomas J. Mitchell
- & Sam Behjati
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Article
| Open AccessNotch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer
Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC) and the mechanisms driving benefit are poorly understood. Here, the authors show that elevated Notch signaling predicts clinical benefit in ICB in relapsed SCLC.
- Nitin Roper
- , Moises J. Velez
- & Anish Thomas
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Article
| Open AccessComprehensive identification of transposable element insertions using multiple sequencing technologies
Identification of transposable element (TE) insertions from whole genome sequencing data remains challenging. Here the authors developed a comprehensive TE insertion detection algorithm xTea that can be applied to both short-read and long-read sequencing data.
- Chong Chu
- , Rebeca Borges-Monroy
- & Peter J. Park
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Article
| Open AccessEnhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS
Liquid biopsies allow the non-invasive detection of somatic mutations from tumours. Here, the authors develop and test MSK-ACCESS, an NGS-based clinical assay for identifying low frequency mutations in 129 genes and describe how it benefits patients in the clinic.
- A. Rose Brannon
- , Gowtham Jayakumaran
- & Ryma Benayed
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Article
| Open AccessMulti-omics profiling of primary small cell carcinoma of the esophagus reveals RB1 disruption and additional molecular subtypes
Primary small cell carcinoma of the oesophagus has a poor prognosis, and has not been fully characterised molecularly. Here, the authors study the disease using multi-omics technology and find frequent RB1 disruptions and similarities to small cell lung cancer, opening potential therapeutic avenues.
- Renda Li
- , Zhenlin Yang
- & Jie He