34 results on '"Hiley CT"'
Search Results
2. Deep cell phenotyping and spatial analysis of multiplexed imaging with TRACERx-PHLEX.
- Author
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Magness A, Colliver E, Enfield KSS, Lee C, Shimato M, Daly E, Moore DA, Sivakumar M, Valand K, Levi D, Hiley CT, Hobson PS, van Maldegem F, Reading JL, Quezada SA, Downward J, Sahai E, Swanton C, and Angelova M
- Subjects
- Humans, Image Processing, Computer-Assisted methods, Animals, Software, Spatial Analysis, Single-Cell Analysis methods, Phenotype, Mice, Image Cytometry methods, Deep Learning
- Abstract
The growing scale and dimensionality of multiplexed imaging require reproducible and comprehensive yet user-friendly computational pipelines. TRACERx-PHLEX performs deep learning-based cell segmentation (deep-imcyto), automated cell-type annotation (TYPEx) and interpretable spatial analysis (Spatial-PHLEX) as three independent but interoperable modules. PHLEX generates single-cell identities, cell densities within tissue compartments, marker positivity calls and spatial metrics such as cellular barrier scores, along with summary graphs and spatial visualisations. PHLEX was developed using imaging mass cytometry (IMC) in the TRACERx study, validated using published Co-detection by indexing (CODEX), IMC and orthogonal data and benchmarked against state-of-the-art approaches. We evaluated its use on different tissue types, tissue fixation conditions, image sizes and antibody panels. As PHLEX is an automated and containerised Nextflow pipeline, manual assessment, programming skills or pathology expertise are not essential. PHLEX offers an end-to-end solution in a growing field of highly multiplexed data and provides clinically relevant insights., (© 2024. The Author(s).)
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- 2024
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3. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
- Author
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Hobor S, Al Bakir M, Hiley CT, Skrzypski M, Frankell AM, Bakker B, Watkins TBK, Markovets A, Dry JR, Brown AP, van der Aart J, van den Bos H, Spierings D, Oukrif D, Novelli M, Chakrabarti T, Rabinowitz AH, Ait Hassou L, Litière S, Kerr DL, Tan L, Kelly G, Moore DA, Renshaw MJ, Venkatesan S, Hill W, Huebner A, Martínez-Ruiz C, Black JRM, Wu W, Angelova M, McGranahan N, Downward J, Chmielecki J, Barrett C, Litchfield K, Chew SK, Blakely CM, de Bruin EC, Foijer F, Vousden KH, Bivona TG, Hynds RE, Kanu N, Zaccaria S, Grönroos E, and Swanton C
- Subjects
- Humans, Animals, Mice, Drug Resistance, Neoplasm genetics, Cell Line, Tumor, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung pathology, Molecular Targeted Therapy methods, Female, DNA Copy Number Variations, Male, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Chromosomal Instability, Lung Neoplasms genetics, Lung Neoplasms drug therapy, Lung Neoplasms pathology, ErbB Receptors genetics, ErbB Receptors metabolism, ErbB Receptors antagonists & inhibitors, Mutation
- Abstract
The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies., (© 2024. The Author(s).)
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- 2024
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4. Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING.
- Author
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Takaki T, Millar R, Hiley CT, and Boulton SJ
- Subjects
- Humans, Phosphorylation, DNA Replication radiation effects, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, Interferon Regulatory Factor-3 metabolism, Interferon Regulatory Factor-3 genetics, Immunity, Innate radiation effects, DNA Damage, HEK293 Cells, Animals, Radiation, Ionizing, HeLa Cells, Nucleotidyltransferases metabolism, Nucleotidyltransferases genetics, Membrane Proteins metabolism, Membrane Proteins genetics, Signal Transduction, Micronuclei, Chromosome-Defective radiation effects, Nucleotides, Cyclic metabolism, Chromosome Segregation
- Abstract
The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in innate immune responses to viral infection and inhibition of autoimmunity. Recent studies have suggested that micronuclei formed by genotoxic stress can activate innate immune signaling via the cGAS-STING pathway. Here, we investigated cGAS localization, activation, and downstream signaling from micronuclei induced by ionizing radiation, replication stress, and chromosome segregation errors. Although cGAS localized to ruptured micronuclei via binding to self-DNA, we failed to observe cGAS activation; cGAMP production; downstream phosphorylation of STING, TBK1, or IRF3; nuclear accumulation of IRF3; or expression of interferon-stimulated genes. Failure to activate the cGAS-STING pathway was observed across primary and immortalized cell lines, which retained the ability to activate the cGAS-STING pathway in response to dsDNA or modified vaccinia virus infection. We provide evidence that micronuclei formed by genotoxic insults contain histone-bound self-DNA, which we show is inhibitory to cGAS activation in cells., Competing Interests: Declaration of interests S.J.B. is a co-founder, VP Science Strategy, and shareholder at Artios Pharma Ltd. C.T.H. acknowledges grant support from Hoffman La Roche, has received speaker fees from AstraZeneca and Eli Lilly, and has a paid advisory role for GenesisCare UK., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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5. Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer.
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Enfield KSS, Colliver E, Lee C, Magness A, Moore DA, Sivakumar M, Grigoriadis K, Pich O, Karasaki T, Hobson PS, Levi D, Veeriah S, Puttick C, Nye EL, Green M, Dijkstra KK, Shimato M, Akarca AU, Marafioti T, Salgado R, Hackshaw A, Jamal-Hanjani M, van Maldegem F, McGranahan N, Glass B, Pulaski H, Walk E, Reading JL, Quezada SA, Hiley CT, Downward J, Sahai E, Swanton C, and Angelova M
- Subjects
- Humans, T-Lymphocytes immunology, Myeloid Cells immunology, Female, Male, Immune Evasion, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms genetics, Tumor Microenvironment immunology
- Abstract
Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis., Significance: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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6. The evolution of non-small cell lung cancer metastases in TRACERx.
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Al Bakir M, Huebner A, Martínez-Ruiz C, Grigoriadis K, Watkins TBK, Pich O, Moore DA, Veeriah S, Ward S, Laycock J, Johnson D, Rowan A, Razaq M, Akther M, Naceur-Lombardelli C, Prymas P, Toncheva A, Hessey S, Dietzen M, Colliver E, Frankell AM, Bunkum A, Lim EL, Karasaki T, Abbosh C, Hiley CT, Hill MS, Cook DE, Wilson GA, Salgado R, Nye E, Stone RK, Fennell DA, Price G, Kerr KM, Naidu B, Middleton G, Summers Y, Lindsay CR, Blackhall FH, Cave J, Blyth KG, Nair A, Ahmed A, Taylor MN, Procter AJ, Falzon M, Lawrence D, Navani N, Thakrar RM, Janes SM, Papadatos-Pastos D, Forster MD, Lee SM, Ahmad T, Quezada SA, Peggs KS, Van Loo P, Dive C, Hackshaw A, Birkbak NJ, Zaccaria S, Jamal-Hanjani M, McGranahan N, and Swanton C
- Subjects
- Humans, Cohort Studies, Disease Progression, Neoplasm Recurrence, Local, Carcinoma, Non-Small-Cell Lung pathology, Clonal Evolution, Clone Cells pathology, Evolution, Molecular, Lung Neoplasms pathology, Neoplasm Metastasis diagnosis, Neoplasm Metastasis pathology
- Abstract
Metastatic disease is responsible for the majority of cancer-related deaths
1 . We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse., (© 2023. The Author(s).)- Published
- 2023
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7. The evolution of lung cancer and impact of subclonal selection in TRACERx.
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Frankell AM, Dietzen M, Al Bakir M, Lim EL, Karasaki T, Ward S, Veeriah S, Colliver E, Huebner A, Bunkum A, Hill MS, Grigoriadis K, Moore DA, Black JRM, Liu WK, Thol K, Pich O, Watkins TBK, Naceur-Lombardelli C, Cook DE, Salgado R, Wilson GA, Bailey C, Angelova M, Bentham R, Martínez-Ruiz C, Abbosh C, Nicholson AG, Le Quesne J, Biswas D, Rosenthal R, Puttick C, Hessey S, Lee C, Prymas P, Toncheva A, Smith J, Xing W, Nicod J, Price G, Kerr KM, Naidu B, Middleton G, Blyth KG, Fennell DA, Forster MD, Lee SM, Falzon M, Hewish M, Shackcloth MJ, Lim E, Benafif S, Russell P, Boleti E, Krebs MG, Lester JF, Papadatos-Pastos D, Ahmad T, Thakrar RM, Lawrence D, Navani N, Janes SM, Dive C, Blackhall FH, Summers Y, Cave J, Marafioti T, Herrero J, Quezada SA, Peggs KS, Schwarz RF, Van Loo P, Miedema DM, Birkbak NJ, Hiley CT, Hackshaw A, Zaccaria S, Jamal-Hanjani M, McGranahan N, and Swanton C
- Subjects
- Humans, Adenocarcinoma of Lung etiology, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology, Mutation, Neoplasm Recurrence, Local genetics, Phylogeny, Treatment Outcome, Smoking genetics, Smoking physiopathology, Mutagenesis, DNA Copy Number Variations, Carcinoma, Non-Small-Cell Lung etiology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms etiology, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Lung cancer is the leading cause of cancer-associated mortality worldwide
1 . Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource., (© 2023. The Author(s).)- Published
- 2023
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8. Antibodies against endogenous retroviruses promote lung cancer immunotherapy.
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Ng KW, Boumelha J, Enfield KSS, Almagro J, Cha H, Pich O, Karasaki T, Moore DA, Salgado R, Sivakumar M, Young G, Molina-Arcas M, de Carné Trécesson S, Anastasiou P, Fendler A, Au L, Shepherd STC, Martínez-Ruiz C, Puttick C, Black JRM, Watkins TBK, Kim H, Shim S, Faulkner N, Attig J, Veeriah S, Magno N, Ward S, Frankell AM, Al Bakir M, Lim EL, Hill MS, Wilson GA, Cook DE, Birkbak NJ, Behrens A, Yousaf N, Popat S, Hackshaw A, Hiley CT, Litchfield K, McGranahan N, Jamal-Hanjani M, Larkin J, Lee SH, Turajlic S, Swanton C, Downward J, and Kassiotis G
- Subjects
- Animals, Humans, Mice, Adenocarcinoma of Lung immunology, Adenocarcinoma of Lung therapy, Adenocarcinoma of Lung virology, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung therapy, Carcinoma, Non-Small-Cell Lung virology, Disease Models, Animal, Lung immunology, Tumor Microenvironment, B-Lymphocytes immunology, Cohort Studies, Antibodies immunology, Antibodies therapeutic use, Endogenous Retroviruses immunology, Immunotherapy methods, Lung Neoplasms immunology, Lung Neoplasms therapy, Lung Neoplasms virology
- Abstract
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)
1,2 . Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2 . Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3 . We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response., (© 2023. The Author(s).)- Published
- 2023
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9. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.
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Abbosh C, Frankell AM, Harrison T, Kisistok J, Garnett A, Johnson L, Veeriah S, Moreau M, Chesh A, Chaunzwa TL, Weiss J, Schroeder MR, Ward S, Grigoriadis K, Shahpurwalla A, Litchfield K, Puttick C, Biswas D, Karasaki T, Black JRM, Martínez-Ruiz C, Bakir MA, Pich O, Watkins TBK, Lim EL, Huebner A, Moore DA, Godin-Heymann N, L'Hernault A, Bye H, Odell A, Roberts P, Gomes F, Patel AJ, Manzano E, Hiley CT, Carey N, Riley J, Cook DE, Hodgson D, Stetson D, Barrett JC, Kortlever RM, Evan GI, Hackshaw A, Daber RD, Shaw JA, Aerts HJWL, Licon A, Stahl J, Jamal-Hanjani M, Birkbak NJ, McGranahan N, and Swanton C
- Subjects
- Humans, Cohort Studies, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Phylogeny, Liquid Biopsy, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Circulating Tumor DNA blood, Circulating Tumor DNA genetics, Lung Neoplasms blood, Lung Neoplasms genetics, Lung Neoplasms pathology, Mutation, Neoplasm Metastasis diagnosis, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology, Small Cell Lung Carcinoma pathology
- Abstract
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy
1 . The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2 . A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy., (© 2023. The Author(s).)- Published
- 2023
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10. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.
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Karasaki T, Moore DA, Veeriah S, Naceur-Lombardelli C, Toncheva A, Magno N, Ward S, Bakir MA, Watkins TBK, Grigoriadis K, Huebner A, Hill MS, Frankell AM, Abbosh C, Puttick C, Zhai H, Gimeno-Valiente F, Saghafinia S, Kanu N, Dietzen M, Pich O, Lim EL, Martínez-Ruiz C, Black JRM, Biswas D, Campbell BB, Lee C, Colliver E, Enfield KSS, Hessey S, Hiley CT, Zaccaria S, Litchfield K, Birkbak NJ, Cadieux EL, Demeulemeester J, Van Loo P, Adusumilli PS, Tan KS, Cheema W, Sanchez-Vega F, Jones DR, Rekhtman N, Travis WD, Hackshaw A, Marafioti T, Salgado R, Le Quesne J, Nicholson AG, McGranahan N, Swanton C, and Jamal-Hanjani M
- Subjects
- Humans, Neoplasm Recurrence, Local pathology, Disease Progression, DNA Helicases, Nuclear Proteins, Transcription Factors, Lung Neoplasms genetics, Lung Neoplasms pathology, Adenocarcinoma genetics, Adenocarcinoma pathology, Adenocarcinoma of Lung genetics
- Abstract
Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk., (© 2023. The Author(s) under exclusive license to Springer Nature America, Inc.)
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- 2023
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11. Dose-Response Analysis Describes Particularly Rapid Repopulation of Non-Small Cell Lung Cancer during Concurrent Chemoradiotherapy.
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Huang HT, Nix MG, Brand DH, Cobben D, Hiley CT, Fenwick JD, and Hawkins MA
- Abstract
(1) Purpose: We analysed overall survival (OS) rates following radiotherapy (RT) and chemo-RT of locally-advanced non-small cell lung cancer (LA-NSCLC) to investigate whether tumour repopulation varies with treatment-type, and to further characterise the low α / β ratio found in a previous study. (2) Materials and methods: Our dataset comprised 2-year OS rates for 4866 NSCLC patients (90.5% stage IIIA/B) belonging to 51 cohorts treated with definitive RT, sequential chemo-RT (sCRT) or concurrent chemo-RT (cCRT) given in doses-per-fraction ≤3 Gy over 16-60 days. Progressively more detailed dose-response models were fitted, beginning with a probit model, adding chemotherapy effects and survival-limiting toxicity, and allowing tumour repopulation and α / β to vary with treatment-type and stage. Models were fitted using the maximum-likelihood technique, then assessed via the Akaike information criterion and cross-validation. (3) Results: The most detailed model performed best, with repopulation offsetting 1.47 Gy/day (95% confidence interval, CI: 0.36, 2.57 Gy/day) for cCRT but only 0.30 Gy/day (95% CI: 0.18, 0.47 Gy/day) for RT/sCRT. The overall fitted tumour α / β ratio was 3.0 Gy (95% CI: 1.6, 5.6 Gy). (4) Conclusion: The fitted repopulation rates indicate that cCRT schedule durations should be shortened to the minimum in which prescribed doses can be tolerated. The low α / β ratio suggests hypofractionation should be efficacious.
- Published
- 2022
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12. A Novel and Automated Approach to Classify Radiation Induced Lung Tissue Damage on CT Scans.
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Szmul A, Chandy E, Veiga C, Jacob J, Stavropoulou A, Landau D, Hiley CT, and McClelland JR
- Abstract
Radiation-induced lung damage (RILD) is a common side effect of radiotherapy (RT). The ability to automatically segment, classify, and quantify different types of lung parenchymal change is essential to uncover underlying patterns of RILD and their evolution over time. A RILD dedicated tissue classification system was developed to describe lung parenchymal tissue changes on a voxel-wise level. The classification system was automated for segmentation of five lung tissue classes on computed tomography (CT) scans that described incrementally increasing tissue density, ranging from normal lung (Class 1) to consolidation (Class 5). For ground truth data generation, we employed a two-stage data annotation approach, akin to active learning. Manual segmentation was used to train a stage one auto-segmentation method. These results were manually refined and used to train the stage two auto-segmentation algorithm. The stage two auto-segmentation algorithm was an ensemble of six 2D Unets using different loss functions and numbers of input channels. The development dataset used in this study consisted of 40 cases, each with a pre-radiotherapy, 3-, 6-, 12-, and 24-month follow-up CT scans ( n = 200 CT scans). The method was assessed on a hold-out test dataset of 6 cases ( n = 30 CT scans). The global Dice score coefficients (DSC) achieved for each tissue class were: Class (1) 99% and 98%, Class (2) 71% and 44%, Class (3) 56% and 26%, Class (4) 79% and 47%, and Class (5) 96% and 92%, for development and test subsets, respectively. The lowest values for the test subsets were caused by imaging artefacts or reflected subgroups that occurred infrequently and with smaller overall parenchymal volumes. We performed qualitative evaluation on the test dataset presenting manual and auto-segmentation to a blinded independent radiologist to rate them as 'acceptable', 'minor disagreement' or 'major disagreement'. The auto-segmentation ratings were similar to the manual segmentation, both having approximately 90% of cases rated as acceptable. The proposed framework for auto-segmentation of different lung tissue classes produces acceptable results in the majority of cases and has the potential to facilitate future large studies of RILD.
- Published
- 2022
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13. Using DNA sequencing data to quantify T cell fraction and therapy response.
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Bentham R, Litchfield K, Watkins TBK, Lim EL, Rosenthal R, Martínez-Ruiz C, Hiley CT, Bakir MA, Salgado R, Moore DA, Jamal-Hanjani M, Swanton C, and McGranahan N
- Subjects
- Adenocarcinoma of Lung diagnosis, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung immunology, Adenocarcinoma of Lung therapy, Aspartic Acid Endopeptidases genetics, Cohort Studies, Exome genetics, Female, Humans, Lymphocytes, Tumor-Infiltrating immunology, Male, Mutation, Neoplasms diagnosis, Neoplasms genetics, Prognosis, Receptors, Antigen, T-Cell, alpha-beta genetics, Exome Sequencing economics, Immunotherapy, Neoplasms immunology, Neoplasms therapy, T-Lymphocytes cytology, T-Lymphocytes metabolism
- Abstract
The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy
1,2 . However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
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14. CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer.
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Walls GM, Oughton JB, Chalmers AJ, Brown S, Collinson F, Forster MD, Franks KN, Gilbert A, Hanna GG, Hannaway N, Harrow S, Haswell T, Hiley CT, Hinsley S, Krebs M, Murden G, Phillip R, Ryan AJ, Salem A, Sebag-Montefoire D, Shaw P, Twelves CJ, Walker K, Young RJ, Faivre-Finn C, and Greystoke A
- Abstract
Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)
- Published
- 2020
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15. Publisher Correction: Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.
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Joshi K, de Massy MR, Ismail M, Reading JL, Uddin I, Woolston A, Hatipoglu E, Oakes T, Rosenthal R, Peacock T, Ronel T, Noursadeghi M, Turati V, Furness AJS, Georgiou A, Wong YNS, Ben Aissa A, Sunderland MW, Jamal-Hanjani M, Veeriah S, Birkbak NJ, Wilson GA, Hiley CT, Ghorani E, Guerra-Assunção JA, Herrero J, Enver T, Hadrup SR, Hackshaw A, Peggs KS, McGranahan N, Swanton C, Quezada SA, and Chain B
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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16. Publisher Correction: A clonal expression biomarker associates with lung cancer mortality.
- Author
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Biswas D, Birkbak NJ, Rosenthal R, Hiley CT, Lim EL, Papp K, Boeing S, Krzystanek M, Djureinovic D, La Fleur L, Greco M, Döme B, Fillinger J, Brunnström H, Wu Y, Moore DA, Skrzypski M, Abbosh C, Litchfield K, Al Bakir M, Watkins TBK, Veeriah S, Wilson GA, Jamal-Hanjani M, Moldvay J, Botling J, Chinnaiyan AM, Micke P, Hackshaw A, Bartek J, Csabai I, Szallasi Z, Herrero J, McGranahan N, and Swanton C
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
- Full Text
- View/download PDF
17. Geospatial immune variability illuminates differential evolution of lung adenocarcinoma.
- Author
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AbdulJabbar K, Raza SEA, Rosenthal R, Jamal-Hanjani M, Veeriah S, Akarca A, Lund T, Moore DA, Salgado R, Al Bakir M, Zapata L, Hiley CT, Officer L, Sereno M, Smith CR, Loi S, Hackshaw A, Marafioti T, Quezada SA, McGranahan N, Le Quesne J, Swanton C, and Yuan Y
- Subjects
- Adenocarcinoma of Lung immunology, Adenocarcinoma of Lung pathology, Antigens, Neoplasm immunology, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Deep Learning, Exome genetics, Female, Humans, Male, Middle Aged, Mutation genetics, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Neoplasm Staging, RNA-Seq, Recurrence, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Exome Sequencing, Adenocarcinoma of Lung genetics, Antigens, Neoplasm genetics, Carcinoma, Non-Small-Cell Lung genetics, Neoplasm Recurrence, Local genetics
- Abstract
Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape
1-5 . However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort6 . Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer-stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes.- Published
- 2020
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18. The T cell differentiation landscape is shaped by tumour mutations in lung cancer.
- Author
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Ghorani E, Reading JL, Henry JY, Massy MR, Rosenthal R, Turati V, Joshi K, Furness AJS, Ben Aissa A, Saini SK, Ramskov S, Georgiou A, Sunderland MW, Wong YNS, Mucha MV, Day W, Galvez-Cancino F, Becker PD, Uddin I, Oakes T, Ismail M, Ronel T, Woolston A, Jamal-Hanjani M, Veeriah S, Birkbak NJ, Wilson GA, Litchfield K, Conde L, Guerra-Assunção JA, Blighe K, Biswas D, Salgado R, Lund T, Bakir MA, Moore DA, Hiley CT, Loi S, Sun Y, Yuan Y, AbdulJabbar K, Turajilic S, Herrero J, Enver T, Hadrup SR, Hackshaw A, Peggs KS, McGranahan N, Chain B, Swanton C, and Quezada SA
- Subjects
- B7-H1 Antigen genetics, Biomarkers, Tumor genetics, Cell Differentiation genetics, Humans, Mutation, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
- Abstract
Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC., Competing Interests: Competing interest statement S.A.Q., K.S.P. and C.S. are co-founders of Achilles Therapeutics. C.S. receives grant support from Pfizer, AstraZeneca, BMS, Roche-Ventana and Boehringer-Ingelheim. C.S. has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, and the Sarah Cannon Research Institute. C.S. is a shareholder of Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options in and is co-founder of Achilles Therapeutics. R.R., N.M. and G.A.W. have stock options in and have consulted for Achilles Therapeutics. J.L.R and M.A.B have consulted for Achilles Therapeutics. P.D.B and M.W.S are employees of Achilles Therapeutics.
- Published
- 2020
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19. Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.
- Author
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Joshi K, de Massy MR, Ismail M, Reading JL, Uddin I, Woolston A, Hatipoglu E, Oakes T, Rosenthal R, Peacock T, Ronel T, Noursadeghi M, Turati V, Furness AJS, Georgiou A, Wong YNS, Ben Aissa A, Sunderland MW, Jamal-Hanjani M, Veeriah S, Birkbak NJ, Wilson GA, Hiley CT, Ghorani E, Guerra-Assunção JA, Herrero J, Enver T, Hadrup SR, Hackshaw A, Peggs KS, McGranahan N, Swanton C, Quezada SA, and Chain B
- Subjects
- Aged, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung therapy, Female, Humans, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, Male, Middle Aged, Mutation, Receptors, Antigen, T-Cell immunology, Carcinoma, Non-Small-Cell Lung genetics, Genetic Heterogeneity, Immunotherapy, Adoptive, Receptors, Antigen, T-Cell genetics
- Abstract
Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8
+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.- Published
- 2019
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20. A clonal expression biomarker associates with lung cancer mortality.
- Author
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Biswas D, Birkbak NJ, Rosenthal R, Hiley CT, Lim EL, Papp K, Boeing S, Krzystanek M, Djureinovic D, La Fleur L, Greco M, Döme B, Fillinger J, Brunnström H, Wu Y, Moore DA, Skrzypski M, Abbosh C, Litchfield K, Al Bakir M, Watkins TBK, Veeriah S, Wilson GA, Jamal-Hanjani M, Moldvay J, Botling J, Chinnaiyan AM, Micke P, Hackshaw A, Bartek J, Csabai I, Szallasi Z, Herrero J, McGranahan N, and Swanton C
- Subjects
- Aged, Biomarkers, Tumor genetics, DNA Copy Number Variations genetics, Disease-Free Survival, Exome genetics, Female, Gene Expression Regulation, Neoplastic, Genetic Heterogeneity, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Risk Factors, Exome Sequencing, Clonal Evolution genetics, Lung Neoplasms genetics, Prognosis, Transcriptome genetics
- Abstract
An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage
1 . Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2-6 . Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.- Published
- 2019
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21. Neoantigen-directed immune escape in lung cancer evolution.
- Author
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Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, Lund T, Tanić M, Reading JL, Joshi K, Henry JY, Ghorani E, Wilson GA, Birkbak NJ, Jamal-Hanjani M, Veeriah S, Szallasi Z, Loi S, Hellmann MD, Feber A, Chain B, Herrero J, Quezada SA, Demeulemeester J, Van Loo P, Beck S, McGranahan N, and Swanton C
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma immunology, Adenocarcinoma pathology, Antigen Presentation immunology, Antigens, Neoplasm genetics, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell immunology, Carcinoma, Squamous Cell pathology, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Lung Neoplasms genetics, Lymphocytes, Tumor-Infiltrating immunology, Male, Prognosis, Tumor Microenvironment immunology, Antigens, Neoplasm immunology, Evolution, Molecular, Lung Neoplasms immunology, Lung Neoplasms pathology, Tumor Escape immunology
- Abstract
The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.
- Published
- 2019
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22. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.
- Author
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McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK, Wilson GA, Birkbak NJ, Veeriah S, Van Loo P, Herrero J, and Swanton C
- Subjects
- Adult, Aged, Aged, 80 and over, Antigen Presentation, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung therapy, Cohort Studies, Female, HLA Antigens immunology, Humans, Loss of Heterozygosity, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms therapy, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Carcinoma, Non-Small-Cell Lung immunology, HLA Antigens genetics, Lung Neoplasms immunology, Tumor Escape
- Abstract
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT., (Copyright © 2017 The Francis Crick Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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23. Tracking the Evolution of Non-Small-Cell Lung Cancer.
- Author
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Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O'Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, and Swanton C
- Subjects
- Carcinoma, Non-Small-Cell Lung mortality, DNA Copy Number Variations, Disease-Free Survival, Evolution, Molecular, Exome, Female, Humans, Lung Neoplasms mortality, Male, Phylogeny, Prognosis, Prospective Studies, Risk Factors, Sequence Analysis, DNA methods, Carcinoma, Non-Small-Cell Lung genetics, Chromosomal Instability, Genetic Heterogeneity, Lung Neoplasms genetics, Mutation, Neoplasm Recurrence, Local genetics
- Abstract
Background: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC., Methods: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival., Results: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10
-4 ), which remained significant in multivariate analysis., Conclusions: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).- Published
- 2017
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24. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease.
- Author
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Hiley CT, Le Quesne J, Santis G, Sharpe R, de Castro DG, Middleton G, and Swanton C
- Subjects
- Anaplastic Lymphoma Kinase, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung genetics, ErbB Receptors analysis, ErbB Receptors genetics, Humans, Lung Neoplasms genetics, Mutation, Receptor Protein-Tyrosine Kinases genetics, Severity of Illness Index, Carcinoma, Non-Small-Cell Lung pathology, High-Throughput Nucleotide Sequencing methods, Lung Neoplasms pathology
- Abstract
Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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25. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
- Author
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McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, and Swanton C
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma genetics, Adenocarcinoma of Lung, Aged, Aged, 80 and over, Antigens, Neoplasm genetics, Antineoplastic Agents therapeutic use, CTLA-4 Antigen immunology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Cell Cycle Checkpoints immunology, Female, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lymphocytes, Tumor-Infiltrating immunology, Male, Melanoma immunology, Middle Aged, Mutation, Programmed Cell Death 1 Receptor immunology, Skin Neoplasms immunology, Adenocarcinoma immunology, Antigens, Neoplasm immunology, CD4-Positive T-Lymphocytes immunology, Immunologic Surveillance, Lung Neoplasms immunology
- Abstract
As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
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26. Pruning Cancer's Evolutionary Tree with Lesion-Directed Therapy.
- Author
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Hiley CT and Swanton C
- Subjects
- High-Throughput Nucleotide Sequencing, Humans, Colorectal Neoplasms, DNA, Neoplasm genetics
- Abstract
Next-generation sequencing of spatially and temporally separated biopsies and circulating tumor DNA directs therapy in response to tumor evolution and acquired resistance in colorectal cancer., (©2016 American Association for Cancer Research.)
- Published
- 2016
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27. Cognitive Impairment in Survivors of Irradiated Brain Tumors Is Multifactorial: Implications of Polypharmacy With Antiepileptics?
- Author
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Hiley CT
- Subjects
- Female, Humans, Male, Brain Neoplasms drug therapy, Brain Neoplasms radiotherapy, Cognition Disorders drug therapy, Indans therapeutic use, Piperidines therapeutic use
- Published
- 2015
- Full Text
- View/download PDF
28. Evolutionary Precision Medicine: A Role for Repeat Epidermal Growth Factor Receptor Analysis in ALK-Rearranged Lung Adenocarcinoma?
- Author
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Birkbak NJ, Hiley CT, and Swanton C
- Subjects
- Female, Humans, Male, Adenocarcinoma genetics, Adenocarcinoma pathology, ErbB Receptors genetics, Gene Rearrangement, Lung Neoplasms genetics, Lung Neoplasms pathology, Mutation, Oncogene Proteins, Fusion genetics, Receptor Protein-Tyrosine Kinases genetics
- Published
- 2015
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29. Can oncology recapitulate paleontology? Lessons from species extinctions.
- Author
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Walther V, Hiley CT, Shibata D, Swanton C, Turner PE, and Maley CC
- Subjects
- Humans, Molecular Targeted Therapy methods, Neoplasms diagnosis, Neoplasms genetics, Neoplasms pathology, Prognosis, Translational Research, Biomedical methods, Tumor Microenvironment, Extinction, Biological, Neoplasms therapy, Paleontology methods
- Abstract
Although we can treat cancers with cytotoxic chemotherapies, target them with molecules that inhibit oncogenic drivers, and induce substantial cell death with radiation, local and metastatic tumours recur, resulting in extensive morbidity and mortality. Indeed, driving a tumour to extinction is difficult. Geographically dispersed species of organisms are perhaps equally resistant to extinction, but >99.9% of species that have ever existed on this planet have become extinct. By contrast, we are nowhere near that level of success in cancer therapy. The phenomena are broadly analogous--in both cases, a genetically diverse population mutates and evolves through natural selection. The goal of cancer therapy is to cause cancer cell population extinction, or at least to limit any further increase in population size, to prevent the tumour burden from overwhelming the patient. However, despite available treatments, complete responses are rare, and partial responses are limited in duration. Many patients eventually relapse with tumours that evolve from cells that survive therapy. Similarly, species are remarkably resilient to environmental change. Paleontology can show us the conditions that lead to extinction and the characteristics of species that make them resistant to extinction. These lessons could be translated to improve cancer therapy and prognosis.
- Published
- 2015
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30. Spatial and temporal cancer evolution: causes and consequences of tumour diversity.
- Author
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Hiley CT and Swanton C
- Subjects
- Disease Progression, Humans, Neoplasms pathology, Phylogeny, Sequence Analysis, DNA, Spatio-Temporal Analysis, Drug Resistance, Neoplasm genetics, Evolution, Molecular, Neoplasms chemistry, Neoplasms genetics, Neoplastic Processes
- Abstract
Our knowledge of the morphological heterogeneity of cancer has recently been augmented by the genomic heterogeneity revealed by the use of next-generation sequencing technology. We now know that no two cancers are alike and that even different regions within the same tumour vary in their composition. Tumours consist of multiple clonal populations and they evolve under Darwinian principles. This review summarizes some of the causes of such diversity and its implication for cancer management., (© 2014 Royal College of Physicians.)
- Published
- 2014
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31. Vascular endothelial growth factor A promotes vaccinia virus entry into host cells via activation of the Akt pathway.
- Author
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Hiley CT, Chard LS, Gangeswaran R, Tysome JR, Briat A, Lemoine NR, and Wang Y
- Subjects
- Animals, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal virology, Cell Line, Tumor, Epithelial Cells virology, Genes, Reporter, Humans, Hypoxia, Mice, Mice, Inbred BALB C, Mice, Nude, RNA Interference, RNA, Small Interfering, Respiratory Mucosa virology, Vaccinia metabolism, Vaccinia virology, Vaccinia virus genetics, Vascular Endothelial Growth Factor A genetics, Viral Tropism, Virus Replication genetics, Proto-Oncogene Proteins c-akt metabolism, Vaccinia virus pathogenicity, Vascular Endothelial Growth Factor A metabolism, Virus Internalization
- Abstract
Vaccinia virus (VV) is an enveloped DNA virus from the poxvirus family and has played a crucial role in the eradication of smallpox. It continues to be used in immunotherapy for the prevention of infectious diseases and treatment of cancer. However, the mechanisms of poxvirus entry, the host factors that affect viral virulence, and the reasons for its natural tropism for tumor cells are incompletely understood. By studying the effect of hypoxia on VV infection, we found that vascular endothelial growth factor A (VEGF-A) augments oncolytic VV cytotoxicity. VEGF derived from tumor cells acts to increase VV internalization, resulting in increased replication and cytotoxicity in an AKT-dependent manner in both tumor cells and normal respiratory epithelial cells. Overexpression of VEGF also enhances VV infection within tumor tissue in vivo after systemic delivery. These results highlight the importance of VEGF expression in VV infection and have potential implications for the design of new strategies to prevent poxvirus infection and the development of future generations of oncolytic VV in combination with conventional or biological therapies.
- Published
- 2013
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32. Methylseleninic acid inhibits HDAC activity in diffuse large B-cell lymphoma cell lines.
- Author
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Kassam S, Goenaga-Infante H, Maharaj L, Hiley CT, Juliger S, and Joel SP
- Subjects
- Blotting, Western, Cell Line, Tumor, Cystine drug effects, Cystine metabolism, Humans, Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors, Selenium metabolism, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism, Histone Deacetylase Inhibitors, Histone Deacetylases metabolism, Lymphoma, B-Cell enzymology, Organoselenium Compounds pharmacology
- Abstract
Purpose: Selenium is a trace element that is fundamental to human health. Research has mainly focussed on its role in cancer prevention, but recent evidence supports its role in established cancer, with high concentrations inducing tumour cell death and non-toxic concentrations sensitising cells to chemotherapy. However, the precise mechanism of selenium action is not clear. The effect of methylseleninic acid (MSA), an organic selenium compound, on histone deacetylase (HDAC) activity in diffuse large B-cell lymphoma cell lines is reported here., Methods: Lymphoma cell lines were exposed to MSA under normoxic and hypoxic conditions. Protein expression was determined by western blotting, HDAC activity and VEGF concentration by fluorimetric and electrochemiluminescence assays, respectively, and intracellular selenium metabolites quantified by mass spectrometry., Results: MSA inhibited HDAC activity, which resulted in the acetylation of histone H3 and α-tubulin. However, cellular metabolism of MSA to methylselenol was required for this effect. Dimethylselenide, the methylation product of methylselenol, was found to be the major intracellular metabolite. MSA also inhibited HIF-1α expression and VEGF secretion, a possible consequence of HDAC inhibition., Conclusion: The ability of methylselenol to inhibit HDAC activity has not been previously reported, thus providing a novel mechanism of selenium action.
- Published
- 2011
- Full Text
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33. Lister strain vaccinia virus, a potential therapeutic vector targeting hypoxic tumours.
- Author
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Hiley CT, Yuan M, Lemoine NR, and Wang Y
- Subjects
- Cell Line, Tumor, Humans, Oncolytic Viruses genetics, Transgenes, Viral Proteins genetics, Virus Replication, Cell Hypoxia, Gene Transfer Techniques, Genetic Vectors, Oncolytic Virotherapy methods, Vaccinia virus genetics
- Abstract
Hypoxia contributes to the aggressive and treatment-resistant phenotype of pancreatic ductal adenocarcinoma. Oncolytic vaccinia virus has potential as an anti-tumour agent, but the ability to lyse hypoxic tumour cells is vital for clinical efficacy. We hypothesized that unique aspects of the poxvirus life cycle would protect it from attenuation in hypoxic conditions. We characterized and compared the viral protein production, viral replication, cytotoxicity and transgene expression of Lister strain vaccinia virus in a panel of pancreatic cancer cell lines after exposure to normoxic or hypoxic conditions. Viral protein production was not affected by hypoxia, and high viral titres were produced in both normoxic and hypoxic conditions. Interestingly, there was a 3.5-fold (P<0.001) and 20-fold (P<0.0001) increase in viral cytotoxicity for CFPac1 and MiaPaca2 cell lines, respectively, in hypoxic conditions. Cytotoxicity was equivalent in the remaining cell lines. Levels of transgene expression (luciferase reporter gene) from the vaccinia viral vector were comparable, regardless of the ambient oxygen concentration. The present study suggests that the vaccinia virus is a promising vector for targeting pancreatic cancer and potentially other hypoxic tumour types.
- Published
- 2010
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34. Expression of vascular endothelial growth factor (VEGF) in locally invasive prostate cancer is prognostic for radiotherapy outcome.
- Author
-
Green MM, Hiley CT, Shanks JH, Bottomley IC, West CM, Cowan RA, and Stratford IJ
- Subjects
- Aged, Disease-Free Survival, Humans, Linear Models, Male, Prognosis, Prostate metabolism, Prostate radiation effects, Retrospective Studies, Treatment Outcome, Neoplasm Proteins metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms radiotherapy, Vascular Endothelial Growth Factor A metabolism
- Abstract
Purpose: Vascular endothelial growth factor (VEGF) is an important hypoxia-inducible pro-angiogenic protein that has been linked with an adverse survival outcome after radiotherapy in other cancer types: we hypothesized that this may also occur in prostate cancer. A retrospective study was, therefore, carried out to evaluate the potential of tumor VEGF expression to predict radiotherapy outcome in patients with high-risk prostate cancer., Methods and Materials: Fifty patients with locally advanced (T3 N0 M0) tumors of Gleason score > or =6, and who received radiotherapy alone as primary treatment for their disease, were studied. Vascular endothelial growth factor expression was assessed on pretreatment diagnostic tumor biopsies using a semiquantitative immunohistochemical scoring system. The results were analyzed in relation to clinicopathologic factors and patient outcome including biochemical failure and disease-specific mortality., Results: High VEGF expression was associated with a poor prognosis: in univariate log rank analysis, VEGF was the only significant prognostic factor for disease-specific survival (p = 0.035). High VEGF expression also associated with increased Gleason score (p = 0.02), but not posttreatment biochemical failure., Conclusion: High tumor expression of VEGF identified patients at high risk of failure of treatment with radiotherapy. These patients might benefit from additional treatment approaches incorporating anti-angiogenic or hypoxia-specific agents.
- Published
- 2007
- Full Text
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