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Article
| Open AccessMutated processes predict immune checkpoint inhibitor therapy benefit in metastatic melanoma
Tumour mutational burden is a biomarker of immune checkpoint inhibitor response, but their association is not fully understood. Here, the authors train classifiers to identify key mutated processes which show stable predictive performance in multiple melanoma cohorts.
- Andrew Patterson
- & Noam Auslander
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Article
| Open AccessMechanistic understanding of human SLFN11
Schlafen 11 serves as an antiviral restriction factor and a predictive biomarker in cancer. Here, the authors use cryoelectron microscopy and biochemical assays to understand tRNA endoribonuclease and DNA binding functions of human Schlafen 11.
- Felix J. Metzner
- , Simon J. Wenzl
- & Katja Lammens
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Article
| Open AccessThe immune landscape of human thymic epithelial tumors
Thymic epithelial tumours represent a heterogenous group of malignancies with varied immune cell infiltration and prognosis. Here authors systematically analyze the phenotypes of both epithelial and immune cells that form these tumours, and identify three major subtypes with different T cell involvement that might affect prognosis.
- Zhongwei Xin
- , Mingjie Lin
- & Pin Wu
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Article
| Open AccessBiomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Biomarkers predictive of response to T cell therapy remain to be better defined. This study identifies potential predictive and pharmacodynamic markers of response to NY-ESO-1 T-cell therapy in a solid tumor that may inform lymphodepletion, cell dose, and strategies to enhance anticancer efficacy.
- Alexandra Gyurdieva
- , Stefan Zajic
- & Ioanna Eleftheriadou
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Article
| Open AccessIntegrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics
The mutational landscape of esophageal squamous cell cancer (ESCC) remains poorly characterised. Here, the authors integrate multiple published datasets and systematically evaluate the mutational signatures and the related genomic and clinical features in ESCC.
- Minghao Li
- , Zicheng Zhang
- & Baosheng Li
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Article
| Open AccessNoninvasive imaging of the tumor immune microenvironment correlates with response to immunotherapy in gastric cancer
Tumour microenvironment has been linked with immunotherapy response in gastric cancer. Here, the authors use CT-based radiomics to predict neutrophils-to-lymphocyte ratio and response to immunotherapy.
- Weicai Huang
- , Yuming Jiang
- & Guoxin Li
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Article
| Open AccessGenome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA
Detection of mutational signatures in cell-free DNA (cfDNA) is challenging due to low sequence coverage and low mutant allele fractions. Here, the authors identify mutational signatures in plasma whole genome sequencing of cancer patients and use machine learning to distinguish them from healthy individuals.
- Jonathan C. M. Wan
- , Dennis Stephens
- & Luis A. Diaz Jr.
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Article
| Open AccessSingle cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma
The components of the glioma immune microenvironment and their roles in promoting tumourigenesis remain poorly understood. Here, the use of single-cell RNA sequencing and multiplexed tissue-imaging in adult and pediatric high-grade gliomas reveals the activity and spatial organization of the immunomodulatory purinergic signaling pathway.
- Shannon Coy
- , Shu Wang
- & Sandro Santagata
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Article
| Open AccessDNA methylation-based epigenetic signatures predict somatic genomic alterations in gliomas
No clinical assay currently exists to classify glioma tumours based on gene expression. Here, the authors develop a DNA methylation-based classifier, Unified Diagnostic Pipeline (UniD) that identifies genomic alterations and gene expression subtypes of gliomas.
- Jie Yang
- , Qianghu Wang
- & Erik P. Sulman
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Article
| Open AccessProteomic analysis reveals key differences between squamous cell carcinomas and adenocarcinomas across multiple tissues
Squamous cell carcinomas are an aggressive cancer type which can occur in multiple organ systems. Here, the authors analyse the proteome of SCC cancers from 17 organs and show commonly dysregulated proteins independent of location.
- Qi Song
- , Ye Yang
- & Yingyong Hou
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Article
| Open AccessIntegration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer
Some cancer patients with impaired HLA-I still respond to immunotherapy. Here the authors combine a cytotoxic gene signature from CD4+ and CD8+ T cells with tumor mutational burden to predict immunotherapy response in NSCLC patients, including those with HLA-LOH.
- Denise Lau
- , Sonal Khare
- & Aly A. Khan
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Article
| Open AccessSpatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression
It is essential to improve our understanding of the features that influence aggressiveness and invasion in high grade gliomas (HGG). Here, the authors characterize dynamic anatomical structures in HGG called oncostreams, which are associated with tumor growth and are regulated by COL1A1.
- Andrea Comba
- , Syed M. Faisal
- & Pedro R. Lowenstein
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Article
| Open AccessClinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets
Sarcomas are rare tumours with many different subtypes and clinical outcomes; a broader knowledge of their genetic features is required. Here, the authors analyse 2138 soft tissue and bone sarcomas across 45 subtypes using MSK-IMPACT targeted sequencing and find genomic groups that are distinct from histological subgroups.
- Benjamin A. Nacev
- , Francisco Sanchez-Vega
- & William D. Tap
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Article
| Open AccessClinical genomic profiling in the management of patients with soft tissue and bone sarcoma
Comprehensive molecular profiles are required to understand and treat sarcomas, which comprise more than 70 different subtypes. Here, the authors profile the genomic landscape of 7494 sarcomas across 44 histologies using targeted panel sequencing and identify potential therapeutic targets.
- Mrinal M. Gounder
- , Narasimhan P. Agaram
- & Dexter X. Jin
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Article
| Open AccessGene expression signatures of individual ductal carcinoma in situ lesions identify processes and biomarkers associated with progression towards invasive ductal carcinoma
Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) remains poorly understood. Here, the authors analyse over 2700 micro-dissected samples using transcriptomics to identify genes that characterise different stages of DCIS to IDC progression, and identify IDC-associated markers within early-stage lesions.
- Clare A. Rebbeck
- , Jian Xian
- & Gregory J. Hannon
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Article
| Open AccessPredicting cancer prognosis and drug response from the tumor microbiome
Computational approaches have been developed to estimate tumor microbial abundances from whole genomic and RNA-sequencing datasets. Here the authors report the predictive value of tumor microbial abundance, alone or in combination with gene expression data, for cancer prognosis and drug response.
- Leandro C. Hermida
- , E. Michael Gertz
- & Eytan Ruppin
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Article
| Open AccessAutomated next-generation profiling of genomic alterations in human cancers
The genomic profiling of tumours has not been widely adopted in the clinic due to technical and practical hurdles. Here, the authors develop PGDx elio tissue complete, a scalable, standardised and FDA-cleared test comprising a targeted gene panel and automated machine-learning analysis, which detects clinically relevant sequence biomarkers in cancer samples.
- Laurel A. Keefer
- , James R. White
- & Mark Sausen
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Article
| Open AccessComprehensive profiling of 1015 patients’ exomes reveals genomic-clinical associations in colorectal cancer
The ChangKang (Heathy Bowel) project was established to collect molecular and clinical information of a thousand Chinese colorectal cancer patients. Here, the authors present the genomic landscape of the ChangKang cohort and find a subgroup of patients defined by abnormal mitochondrial copy numbers.
- Qi Zhao
- , Feng Wang
- & Rui-Hua Xu
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Article
| Open AccessPredictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial
Identification of biomarkers to stratify patients who might benefit from treatment is needed to optimize targeted therapies. Here, based on an analysis of the RANGE trial (NCT02426125), the authors report potentially predictive biomarkers for survival benefit in patients with platinum-refractory advanced urothelial carcinoma treated with the anti-VEGFR2 monoclonal antibody ramucirumab.
- Michiel S. van der Heijden
- , Thomas Powles
- & Alexandra Drakaki
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Article
| Open AccessIntegrative analysis of non-small cell lung cancer patient-derived xenografts identifies distinct proteotypes associated with patient outcomes
With non-small cell lung cancer (NSCLC) being the leading cause of cancer deaths worldwide, the development of targeted therapies remains crucial. Here, the generation and multi-omics characterization of 137 NSCLC patient-derived xenografts provides a resource for potential classifications and targets.
- Shideh Mirhadi
- , Shirley Tam
- & Ming-Sound Tsao
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Article
| Open AccessSingle-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer
Tumour microenvironment profiling during colorectal cancer progression may enable the discovery of therapeutic targets. Here, single cell and spatial RNA sequencing of tumour and adjacent normal tissues reveals an interaction between FAP+ fibroblasts and SPP1+ macrophages that could be disrupted as an immunotherapy strategy.
- Jingjing Qi
- , Hongxiang Sun
- & Bing Su
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Article
| Open AccessSingle-cell transcriptomic analysis suggests two molecularly distinct subtypes of intrahepatic cholangiocarcinoma
The molecular classification and tumour microenvironment in intrahepatic cholangiocarcinoma (iCCA) need further characterisation. Here, the authors perform single cell RNA-sequencing from 14 pairs of iCCA tumours and non-tumour liver tissues and propose S100P and SPP1 as markers for patient classification.
- Guohe Song
- , Yang Shi
- & Qiang Gao
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Article
| Open AccessIntegrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis
Despite acral melanoma being the most common melanoma subtype in non-White individuals, its molecular drivers remain unknown. Here, the authors integrate genomic and clinical data from 104 patients and identify late-arising focal amplifications of chr22q11.21 and LZTR1 as a key tumour promoter in this region.
- Farshad Farshidfar
- , Kahn Rhrissorrakrai
- & Ruth Halaban
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Article
| Open AccessGenetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma
SUMOylation is a post-translational modification that has been shown to be altered in cancer. Here, the authors show that loss of the SUMO isopeptidase SENP6 leads to unrestricted SUMOylation and genomic instability promoting lymphomagenesis and generating vulnerability to PARP inhibition.
- Markus Schick
- , Le Zhang
- & Ulrich Keller
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Article
| Open AccessLipidomic profiling of human serum enables detection of pancreatic cancer
Patients with pancreatic cancer have a poor prognosis, more research is required to identify the disease at an earlier stage. Here, the authors use lipid profiles of blood samples and show that they can distinguish patients with pancreatic cancer from healthy controls.
- Denise Wolrab
- , Robert Jirásko
- & Michal Holčapek
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Article
| Open AccessPlatelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer
The definition of biomarkers to predict therapy responses to immune-checkpoint inhibitors represent an unmet clinical need. Here the authors provide evidences that platelet-derived PD-L1 could serve as a prognostic and predictive biomarker in patients with non-small cell lung cancer.
- Clemens Hinterleitner
- , Jasmin Strähle
- & Lars Zender
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Article
| Open AccessRAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer
Antibody Drug Conjugates (ADCs) are emerging in the field of precision cancer medicine. Here, the authors suggest using endocytosis as a predictive biomarker for response
- Olav Engebraaten
- , Christina Yau
- & Anette Weyergang
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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 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 AccessProfiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy
Targeting the inhibitory receptors (IRs) LAG-3, TIM-3 and TIGIT is a promising immune-oncology approach and the identification of biomarkers of response is crucial. Here, the authors apply automated single-cell count for these IRs in human renal cell carcinoma and investigate the immunogenomic landscape of the disease.
- Kimiharu Takamatsu
- , Nobuyuki Tanaka
- & Mototsugu Oya
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Article
| Open AccessTherapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer
In this study, the authors show that that oncogenic hijacking of PRC1 sensitizes genomically stable Ewing sarcoma cells for PLK1 inhibition alone or in synergy with a microtubule-destabilizing drug via induction of cytokinesis defects, rendering PRC1 a promising, broadly applicable predictive biomarker
- Jing Li
- , Shunya Ohmura
- & Thomas G. P. Grünewald
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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 AccessCisplatin-mediated activation of glucocorticoid receptor induces platinum resistance via MAST1
Glucocorticoid receptor (GR) agonists - used in the treatment of solid malignant tumors to reduce inflammation - could potentially affect the anti-tumor activity of chemotherapy. Here, the authors identify a mechanism of cisplatin resistance observed with GR agonist treatment, and show the binding and activation of GR by cisplatin, which leads to MAST1 activation and subsequent MAPK re-activation.
- Chaoyun Pan
- , JiHoon Kang
- & Sumin Kang
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Article
| Open AccessLarge-scale and high-resolution mass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting
Proteomics can aid in the identification of molecular subtypes in cancers. Here, the authors perform proteomic profiling of 124 paired oesophageal cancer and adjacent non-tumour tissues and identify two subtypes that are associated with patient survival for therapeutic targeting.
- Wei Liu
- , Lei Xie
- & En-Min Li
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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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Matters Arising
| Open AccessReply to: “Inconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets”
- Donghai Xiong
- , Yian Wang
- & Ming You
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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 AccessSingle-molecule amplification-free multiplexed detection of circulating microRNA cancer biomarkers from serum
miRNA profiling from patient blood can be used for cancer diagnosis. Here the authors present an electro-optical nanopore sensing platform which allows sensitive and specific miRNA detection directly in human serum and apply to monitoring of miR-141-3p and miR-375-3p in different stage of prostate cancer.
- Shenglin Cai
- , Thomas Pataillot-Meakin
- & Joshua B. Edel
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Article
| Open AccessIntratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer
The prognostic value of tumor infiltrating lymphocytes in gastric cancer remains controversial. Here the authors show a consistent association between higher density of intratumoral CXCR5+CD8+ T cells and longer overall survival in four different cohorts of patients with gastric cancer.
- Jieti Wang
- , Ruochen Li
- & Hua Huang
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Article
| Open AccessPancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility
ATAC-seq allows for the investigation of chromatin accessibility, a feature which can have important implications for gene regulation. Here the authors present ATAC-array to assess accessibility in human tumours and based on this predict disease prognosis.
- S. Dhara
- , S. Chhangawala
- & S. D. Leach
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Article
| Open AccessMolecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)
The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
- Elizabeth M. Swisher
- , Tanya T. Kwan
- & Iain A. McNeish
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Article
| Open AccessDUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death
Chemoresistance is one of the main challenges for cancer therapy success. Here, the authors show that dual-specificity phosphatase 16 (DUSP16) expression is associated with chemoresistance in several types of cancer through impairing mitochondria-associated apoptosis.
- Heng Boon Low
- , Zhen Lim Wong
- & Yongliang Zhang
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Article
| Open AccessGlycan chip based on structure-switchable DNA linker for on-chip biosynthesis of cancer-associated complex glycans
Current methods for on-chip glycan biosynthesis suffer from analysing products, often resulting in poor purity and yield. Here the authors report a glycan chip developed by introducing a pH-responsive i-motif DNA linker to control the immobilization and isolation of glycans on chips.
- Hye Ryoung Heo
- , Kye Il Joo
- & Hyung Joon Cha
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Article
| Open AccessTumour gene expression signature in primary melanoma predicts long-term outcomes
The identification of prognostic biomarkers can help stratify cancer patients. Here, the authors apply deep RNA sequencing from primary melanomas coupled with long-term clinical outcome data from a prospective multicentre phase III trial, to develop and validate a 121 metastasis-associated gene signature identifying early-stage melanoma patients at higher risk of metastasis and worse survival.
- Manik Garg
- , Dominique-Laurent Couturier
- & Roy Rabbie
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Article
| Open AccessDiagnostic accuracy of cytology for the detection of endometrial cancer in urine and vaginal samples
Postmenopausal bleeding can be an indication of endometrial cancer. Here, the authors combine cytology of urine and vaginal samples from women with postmenopausal bleeding and demonstrate that they can accurately predict endometrial cancer with a sensitivity of 91.7% and specificity of 88.8%.
- Helena O’Flynn
- , Neil A. J. Ryan
- & Emma J. Crosbie
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Article
| Open AccessPlasma cells are enriched in localized prostate cancer in Black men and are associated with improved outcomes
A recent report suggested Black men with prostate cancer were more responsive to immunotherapy. Here, the authors analysed prostate cancer gene expression profiles and show tumours from Black men and men with African ancestry have an increased proportion of plasma cells compared to those of White men and this correlates with improved outcome following treatment.
- Adam B. Weiner
- , Thiago Vidotto
- & Edward M. Schaeffer
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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 AccessNicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung
Smoking is known to impact tumor immunity and promote tumor progression. Here, the authors show that chronic nicotine exposure promotes the lung pre-metastatic niche formation by recruiting pro-tumor N2-neutrophils that release lipocalin-2.
- Abhishek Tyagi
- , Sambad Sharma
- & Kounosuke Watabe
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Article
| Open AccessNon-invasive assessment of telomere maintenance mechanisms in brain tumors
Telomerase expression and the alternative lengthening of telomeres pathway are hallmarks of cancer. Here, the authors show that, in primary brain tumors, these features are correlated with metabolic signatures detectable by metabolic imaging, suggesting that they can be used to non-invasively monitor telomere maintenance in brain tumours.
- Pavithra Viswanath
- , Georgios Batsios
- & Sabrina M. Ronen