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5 results on '"Luke Martinson"'

1. Circulating tumor DNA profiling from breast cancer screening through to metastatic disease

Author

Robert K. Hastings, Kelly L. T. Gleason, Kate Goddard, Justin Stebbing, David S. Guttery, Carlo Palmieri, Karen Page, Charlotte Ions, Mark R Openshaw, Simak Ali, Daniel Fernandez-Garcia, Amelia J Rushton, Luke Martinson, Georgios Nteliopoulos, R. Charles Coombes, Allison Hills, Vilas Parmar, Molly C Gray, L Primrose, Jacqueline A Shaw, National Institute for Health Research, and Imperial College Healthcare NHS Trust- BRC Funding

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Population, Breast Neoplasms, Disease, Circulating Tumor DNA, Breast cancer screening, Internal medicine, Biomarkers, Tumor, medicine, Humans, Nucleic Acid Sequencing, Breast screening, Neoplasm Metastasis, education, skin and connective tissue diseases, Aged, Aged, 80 and over, education.field_of_study, medicine.diagnostic_test, Aromatase Inhibitors, business.industry, Estrogen Receptor alpha, High-Throughput Nucleotide Sequencing, ORIGINAL REPORTS, Middle Aged, Survival Analysis, Drug Resistance, Neoplasm, Circulating tumor DNA, Case-Control Studies, Mutation, Female, Tumor Suppressor Protein p53, business
Abstract

PURPOSE We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer. MATERIALS AND METHODS Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform. RESULTS One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1, TP53, and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations. CONCLUSION We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1, TP53, and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs., Detection of ctDNA increases as breast cancer progresses and predicts poor overall survival in metastatic patients. or ctDNA detection increases as breast cancer progresses and predicts poor overall survival in metastatic patients.

Published
2021

2. Prevalence of ctDNA in early screen-detected breast cancers using highly sensitive and specific dual molecular barcoded personalised mutation assays

Author

Karen Page, Daniel Fernandez-Garcia, Amelia J Rushton, Luke Martinson, Justin Stebbing, Jacqui Shaw, Robert K. Hastings, David S. Guttery, R. C. Coombes, Molly C Gray, Kelly L. T. Gleason, and K. Goddard

Subjects
Screen detected, business.industry, Breast Neoplasms, Hematology, Highly sensitive, Circulating Tumor DNA, Text mining, Oncology, Mutation (genetic algorithm), Mutation, Cancer research, Biomarkers, Tumor, Prevalence, Medicine, Humans, Female, business
Published
2021

3. Comparison of two targeted ultra-deep sequencing technologies for analysis of plasma circulating tumour DNA in endocrine-therapy-resistant breast cancer patients

Author

Jacqueline A Shaw, Justin Stebbing, Robert K. Hastings, Karen Howarth, David S. Guttery, Emma Green, Daniel Fernadez-Garcia, Kelly L. T. Gleason, Luke Martinson, Allison Hills, Nitzan Rosenfeld, Charlotte Ion, Laura M. Kenny, Farah Rehman, R. Charles Coombes, Amelia J Rushton, Karen Page, Andrijac Sanela, Susan Cleator, Georgios Nteliopoulos, Warren Emmett, National Institute for Health Research, and Imperial College Healthcare NHS Trust- BRC Funding

Subjects
Oncology, ESR1 MUTATIONS, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Concordance, Estrogen receptor, Breast Neoplasms, DNA sequencing, Targeted therapy, Circulating Tumor DNA, Breast cancer, Internal medicine, Circulating tumour DNA (ctDNA), medicine, Biomarkers, Tumor, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, LEADING TECHNOLOGIES, Science & Technology, business.industry, Endocrine therapy resistance, Cancer, High-Throughput Nucleotide Sequencing, Reproducibility of Results, 1103 Clinical Sciences, medicine.disease, Metastatic breast cancer, Clinical Trial, CFDNA, CELL-FREE DNA, Next-generation sequencing, CTDNA, Female, business, Life Sciences & Biomedicine, Estrogen receptor alpha
Abstract

PurposeThere is growing interest in the application of circulating tumour DNA (ctDNA) as a sensitive tool for monitoring tumour evolution and guiding targeted therapy in patients with cancer. However, robust comparisons of different platform technologies are still required. Here we compared the InVisionSeq™ ctDNA Assay with the Oncomine™ Breast cfDNA Assay to assess their concordance and feasibility for the detection of mutations in plasma at low (MethodsNinety-six plasma samples from 50 patients with estrogen receptor (ER)-positive metastatic breast cancer (mBC) were profiled using the InVision Assay. Results were compared to the Oncomine assay in 30 samples from 26 patients, where there was sufficient material and variants were covered by both assays. Longitudinal samples were analysed for 8 patients with endocrine resistance.ResultsWe detected alterations in 59/96 samples from 34/50 patients analysed with the InVision assay, most frequently affectingESR1, PIK3CAandTP53. Complete or partial concordance was found in 28/30 samples analysed by both assays, and VAF values were highly correlated. Excellent concordance was found for most genes, and most discordant calls occurred at VAF ESR1andPIK3CA.ConclusionThis study shows that both ultra-deep next-generation sequencing (NGS) technologies can detect genomic alternations even at low VAFs in plasma samples of mBC patients. The strong agreement of the technologies indicates sufficient reproducibility for clinical use as prognosic and predictive biomarker.

Published
2020

4. Author Correction: Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment

Author

Nathaniel Kuse, Essa Y. Baitei, Jin-Li Luo, Alan G. Dawson, Amrita Bajaj, Joanna Działo, Charlotte Poile, Luke Martinson, Annabel J. Sharkey, Gareth A. Wilson, Catrin Pritchard, Jacqui Shaw, Gareth Griffiths, Peter Wells-Jordan, David A. Waller, Min Zhang, Lee Brannan, Edward J. Hollox, Pan De Philip Zhang, Qianqian Sun, Michael Sheaff, Maymun Jama, Apostolos Nakas, Cathy Richards, Aarti Gaba, Tamihiro Kamata, Sara Busacca, Hongji Yang, John Le Quesne, Dean A. Fennell, Charles Swanton, Frank Dudbridge, Aleksandra Bzura, and James Harber

Subjects
Mesothelioma, Lung Neoplasms, Tumour heterogeneity, Pleural Neoplasms, Science, MEDLINE, General Physics and Astronomy, Kaplan-Meier Estimate, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, Exome Sequencing, Cancer genomics, Tumor Microenvironment, medicine, Cluster Analysis, Humans, Author Correction, Multidisciplinary, Tumor Suppressor Proteins, Published Erratum, Clonal architecture, General Chemistry, Prognosis, medicine.disease, Clone Cells, Mutation, Chromosome Deletion
Abstract

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/-3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/-22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.

Published
2021

5. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Author

Nicholas McGranahan, Rachel Rosenthal, Crispin T. Hiley, Andrew J. Rowan, Thomas B.K. Watkins, Gareth A. Wilson, Nicolai J. Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton, Mariam Jamal-Hanjani, Seema Shafi, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Leticia Bosshard-Carter, Pat Gorman, Robert E. Hynds, Gareth Wilson, Stuart Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Andrew Rowan, Hang Xu, Samra Turajlic, Crispin Hiley, Christopher Abbosh, Jacki Goldman, Richard Kevin Stone, Tamara Denner, Nik Matthews, Greg Elgar, Sophia Ward, Marta Costa, Sharmin Begum, Ben Phillimore, Tim Chambers, Emma Nye, Sofia Graca, Maise Al Bakir, Kroopa Joshi, Andrew Furness, Assma Ben Aissa, Yien Ning Sophia Wong, Andy Georgiou, Sergio Quezada, John A. Hartley, Helen L. Lowe, David Lawrence, Martin Hayward, Nikolaos Panagiotopoulos, Shyam Kolvekar, Mary Falzon, Elaine Borg, Teresa Marafioti, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco Novelli, Dahmane Oukrif, Sam M. Janes, Ricky Thakrar, Martin Forster, Tanya Ahmad, Siow Ming Lee, Dionysis Papadatos-Pastos, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Asia Ahmed, Magali Taylor, Junaid Choudhary, Yvonne Summers, Raffaele Califano, Paul Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Phil Crosbie, Stuart Moss, Faiza Idries, Leena Joseph, Paul Bishop, Anshuman Chaturved, Anne Marie Quinn, Helen Doran, Angela Leek, Phil Harrison, Katrina Moore, Rachael Waddington, Juliette Novasio, Fiona Blackhall, Jane Rogan, Elaine Smith, Caroline Dive, Jonathan Tugwood, Ged Brady, Dominic G. Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Babu Naidu, Gerald Langman, Simon Trotter, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Kadiri, Joanne Webb, Gary Middleton, Madava Djearaman, Dean Fennell, Jacqui A. Shaw, John Le Quesne, David Moore, Apostolos Nakas, Sridhar Rathinam, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Girija Anand, Sajid Khan, Anita Amadi, Marianne Nicolson, Keith Kerr, Shirley Palmer, Hardy Remmen, Joy Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, Jason Lester, Alison Edwards, Fiona Morgan, Haydn Adams, Helen Davies, Malgorzata Kornaszewska, Richard Attanoos, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Harriet Bell, Allan Hackshaw, Yenting Ngai, Sean Smith, Nicole Gower, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Emily Shaw, Eric Lim, Paulo De Sousa, Monica Tavares Barbosa, Alex Bowman, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Chiara Proli, Maria Elena Cufari, John Carlo Ronquillo, Angela Kwayie, Harshil Bhayani, Morag Hamilton, Yusura Bakar, Natalie Mensah, Lyn Ambrose, Anand Devaraj, Silviu Buderi, Jonathan Finch, Leire Azcarate, Hema Chavan, Sophie Green, Hillaria Mashinga, Andrew G. Nicholson, Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Veni Ezhil, Babikir Ismail, Melanie Irvin-sellers, Vineet Prakash, Peter Russell, Teresa Light, Tracey Horey, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Patricia Fisher, Allah Dino Keerio, Michael Shackcloth, John Gosney, Pieter Postmus, Sarah Feeney, Julius Asante-Siaw, Hugo J.W.L. Aerts, Stefan Dentro, Christophe Dessimoz, TRACERx Consortium, Swanton, C., Jamal-Hanjani, M., Veeriah, S., Shafi, S., Czyzewska-Khan, J., Johnson, D., Laycock, J., Bosshard-Carter, L., Rosenthal, R., Gorman, P., Hynds, R.E., Wilson, G., Birkbak, N.J., Watkins, TBK, McGranahan, N., Horswell, S., Mitter, R., Escudero, M., Stewart, A., Van Loo, P., Rowan, A., Xu, H., Turajlic, S., Hiley, C., Abbosh, C., Goldman, J., Stone, R.K., Denner, T., Matthews, N., Elgar, G., Ward, S., Costa, M., Begum, S., Phillimore, B., Chambers, T., Nye, E., Graca, S., Al Bakir, M., Joshi, K., Furness, A., Ben Aissa, A., Wong, YNS, Georgiou, A., Quezada, S., Hartley, J.A., Lowe, H.L., Herrero, J., Lawrence, D., Hayward, M., Panagiotopoulos, N., Kolvekar, S., Falzon, M., Borg, E., Marafioti, T., Simeon, C., Hector, G., Smith, A., Aranda, M., Novelli, M., Oukrif, D., Janes, S.M., Thakrar, R., Forster, M., Ahmad, T., Lee, S.M., Papadatos-Pastos, D., Carnell, D., Mendes, R., George, J., Navani, N., Ahmed, A., Taylor, M., Choudhary, J., Summers, Y., Califano, R., Taylor, P., Shah, R., Krysiak, P., Rammohan, K., Fontaine, E., Booton, R., Evison, M., Crosbie, P., Moss, S., Idries, F., Joseph, L., Bishop, P., Chaturved, A., Quinn, A.M., Doran, H., Leek, A., Harrison, P., Moore, K., Waddington, R., Novasio, J., Blackhall, F., Rogan, J., Smith, E., Dive, C., Tugwood, J., Brady, G., Rothwell, D.G., Chemi, F., Pierce, J., Gulati, S., Naidu, B., Langman, G., Trotter, S., Bellamy, M., Bancroft, H., Kerr, A., Kadiri, S., Webb, J., Middleton, G., Djearaman, M., Fennell, D., Shaw, J.A., Le Quesne, J., Moore, D., Nakas, A., Rathinam, S., Monteiro, W., Marshall, H., Nelson, L., Bennett, J., Riley, J., Primrose, L., Martinson, L., Anand, G., Khan, S., Amadi, A., Nicolson, M., Kerr, K., Palmer, S., Remmen, H., Miller, J., Buchan, K., Chetty, M., Gomersall, L., Lester, J., Edwards, A., Morgan, F., Adams, H., Davies, H., Kornaszewska, M., Attanoos, R., Lock, S., Verjee, A., MacKenzie, M., Wilcox, M., Bell, H., Hackshaw, A., Ngai, Y., Smith, S., Gower, N., Ottensmeier, C., Chee, S., Johnson, B., Alzetani, A., Shaw, E., Lim, E., De Sousa, P., Barbosa, M.T., Bowman, A., Jordan, S., Rice, A., Raubenheimer, H., Proli, C., Cufari, M.E., Ronquillo, J.C., Kwayie, A., Bhayani, H., Hamilton, M., Bakar, Y., Mensah, N., Ambrose, L., Devaraj, A., Buderi, S., Finch, J., Azcarate, L., Chavan, H., Green, S., Mashinga, H., Nicholson, A.G., Lau, K., Sheaff, M., Schmid, P., Conibear, J., Ezhil, V., Ismail, B., Irvin-Sellers, M., Prakash, V., Russell, P., Light, T., Horey, T., Danson, S., Bury, J., Edwards, J., Hill, J., Matthews, S., Kitsanta, Y., Suvarna, K., Fisher, P., Keerio, A.D., Shackcloth, M., Gosney, J., Postmus, P., Feeney, S., Asante-Siaw, J., Aerts, HJWL, Dentro, S., and Dessimoz, C.

Subjects
Male, immune-editing, 0301 basic medicine, DOWN-REGULATION, immune-escape, Lung Neoplasms, Loss of Heterozygosity, Cohort Studies, Loss of heterozygosity, HLA Antigens, Carcinoma, Non-Small-Cell Lung, Chromosome instability, MUTATIONAL PROCESSES, 11 Medical and Health Sciences, Aged, 80 and over, Antigen Presentation, cancer evolution, Manchester Cancer Research Centre, bioinformatics, Middle Aged, 3. Good health, Female, loss of heterozygosity, SENSITIVITY, Life Sciences & Biomedicine, Adult, Biochemistry & Molecular Biology, chromosomal instability, Antigen presentation, Locus (genetics), NEOANTIGENS, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, copy number, medicine, Humans, Lung cancer, Aged, Science & Technology, ResearchInstitutes_Networks_Beacons/mcrc, CTLA-4 BLOCKADE, Cell Biology, 06 Biological Sciences, medicine.disease, PD-1 BLOCKADE, neoantigen, lung cancer, 030104 developmental biology, Carcinoma, Non-Small-Cell Lung/genetics, Carcinoma, Non-Small-Cell Lung/immunology, Carcinoma, Non-Small-Cell Lung/pathology, Carcinoma, Non-Small-Cell Lung/therapy, HLA Antigens/genetics, HLA Antigens/immunology, Lung Neoplasms/genetics, Lung Neoplasms/immunology, Lung Neoplasms/pathology, Lung Neoplasms/therapy, Mutation, Tumor Escape, heterogeneity, TRACERx Consortium, DISCOVERY, CELLS, Immunology, RESISTANCE, Developmental Biology
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.

Published
2017

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