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1. Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue

Author

Kevin Litchfield, Stacey Stanislaw, Lavinia Spain, Lisa L. Gallegos, Andrew Rowan, Desiree Schnidrig, Heidi Rosenbaum, Alexandre Harle, Lewis Au, Samantha M. Hill, Zayd Tippu, Jennifer Thomas, Lisa Thompson, Hang Xu, Stuart Horswell, Aoune Barhoumi, Carol Jones, Katherine F. Leith, Daniel L. Burgess, Thomas B.K. Watkins, Emilia Lim, Nicolai J. Birkbak, Philippe Lamy, Iver Nordentoft, Lars Dyrskjøt, Lisa Pickering, Stephen Hazell, Mariam Jamal-Hanjani, James Larkin, Charles Swanton, Nelson R. Alexander, Samra Turajlic, Chris Abbosh, Kai-Keen Shiu, John Bridgewater, Daniel Hochhauser, Martin Forster, Siow-Ming Lee, Tanya Ahmad, Dionysis Papadatos-Pastos, Sam Janes, Peter Van Loo, Katey Enfield, Nicholas McGranahan, Ariana Huebner, Sergio Quezada, Stephan Beck, Peter Parker, Henning Walczak, Tariq Enver, Rob Hynds, Mary Falzon, Ian Proctor, Ron Sinclair, Chi-wah Lok, Zoe Rhodes, David Moore, Teresa Marafioti, Elaine Borg, Miriam Mitchison, Reena Khiroya, Giorgia Trevisan, Peter Ellery, Mark Linch, Sebastian Brandner, Crispin Hiley, Selvaraju Veeriah, Maryam Razaq, Heather Shaw, Gert Attard, Mita Afroza Akther, Cristina Naceur-Lombardelli, Lizi Manzano, Maise Al-Bakir, Simranpreet Summan, Nnenna Kanu, Sophie Ward, Uzma Asghar, Faye Gishen, Adrian Tookman, Paddy Stone, Caroline Stirling, Andrew Furness, Kim Edmonds, Nikki Hunter, Sarah Sarker, Sarah Vaughan, Mary Mangwende, Karla Pearce, Scott Shepherd, Haixi Yan, Ben Shum, Eleanor Carlyle, Steve Hazell, Annika Fendler, Fiona Byrne, Nadia Yousaf, Sanjay Popat, Olivia Curtis, Gordon Stamp, Antonia Toncheva, Emma Nye, Aida Murra, Justine Korteweg, Nahid Sheikh, Debra Josephs, Ashish Chandra, James Spicer, Ula Mahadeva, Anna Green, Ruby Stewart, Lara-Rose Iredale, Tina Mackay, Ben Deakin, Debra Enting, Sarah Rudman, Sharmistha Ghosh, Lena Karapagniotou, Elias Pintus, Andrew Tutt, Sarah Howlett, Vasiliki Michalarea, James Brenton, Carlos Caldas, Rebecca Fitzgerald, Merche Jimenez-Linan, Elena Provenzano, Alison Cluroe, Grant Stewart, Colin Watts, Richard Gilbertson, Ultan McDermott, Simon Tavare, Emma Beddowes, Patricia Roxburgh, Andrew Biankin, Anthony Chalmers, Sioban Fraser, Karin Oien, Andrew Kidd, Kevin Blyth, Matt Krebs, Fiona Blackhall, Yvonne Summers, Caroline Dive, Richard Marais, Fabio Gomes, Mat Carter, Jo Dransfield, John Le Quesne, Dean Fennell, Jacqui Shaw, Babu Naidu, Shobhit Baijal, Bruce Tanchel, Gerald Langman, Andrew Robinson, Martin Collard, Peter Cockcroft, Charlotte Ferris, Hollie Bancroft, Amy Kerr, Gary Middleton, Joanne Webb, Salma Kadiri, Peter Colloby, Bernard Olisemeke, Rodelaine Wilson, Ian Tomlinson, Sanjay Jogai, Christian Ottensmeier, David Harrison, Massimo Loda, Adrienne Flanagan, Mairead McKenzie, Allan Hackshaw, Jonathan Ledermann, Abby Sharp, Laura Farrelly, and Hayley Bridger

Subjects
tumor sampling, tumor sequencing, representative sampling, molecular profiling, tumor hetereogeneity, biomarkers, Biology (General), QH301-705.5
Abstract

Summary: Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

Published
2020
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2. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Author

Sanjay Popat, Lewis Au, Jan Attig, Catherine Horsfield, Hayley Bridger, Kitty Chan, Haixi Yan, David Moore, Lara-Rose Iredale, Salma Kadiri, Sebastian Brandner, Rebecca C. Fitzgerald, Bruce Tanchel, Maise Al-Bakir, Katey S. S. Enfield, Merche Jimenez-Linan, Andrew P. Robinson, Kim Edmonds, Stuart Horswell, Elena Provenzano, Andrew V. Biankin, Benny Chain, Scott Shepherd, Antonia Toncheva, Carlos Caldas, Gerald Langman, Fabio Gomes, I Puccio, Amy Kerr, Sharmistha Ghosh, Caroline Dive, James Larkin, Siow Ming Lee, Nicholas McGranahan, Peter Ellery, Charlotte Spencer, Dionysis Papadatos-Pastos, Charles Swanton, Maryam Razaq, Richard J. Gilbertson, Rachael Thompson, William Drake, Lyra Del Rosario, Debra Enting, Lisa Pickering, Crispin T. Hiley, David A Moore, Christian H. Ottensmeier, Ehsan Ghorani, Simon Chowdhury, Simon Tavaré, Sophie Ward, Gordon Stamp, Peter J. Parker, Sam M. Janes, Giorgia Trevisan, Mary Falzon, Ultan McDermott, Christopher Abbosh, Fiona Byrne, Kroopa Joshi, Kim Dhillon, George Kassiotis, James L. Reading, Heather Shaw, Tariq Enver, Dean A. Fennell, Jonathan Ledermann, Annika Fendler, Emma Beddowes, Peter Cockcroft, Mary Mangwende, Desiree Schnidrig, Ian Tomlinson, Mark Linch, Ben Challacombe, Vasiliki Michalarea, Yvonne Summers, Fiona H Blackhall, Robert Mason, Emma Nye, Robert E. Hynds, Debra H. Josephs, Mariana Werner Sunderland, Adrian Tookman, Emilia L. Lim, Paddy Stone, Cristina Naceur-Lombardelli, Bernard Olisemeke, Teresa Marafioti, Mat Carter, Grant D. Stewart, Sanjay Jogai, Richard Marais, Imran Uddin, Kevin Litchfield, Daniel Hochhauser, Alexander Polson, William Yang, Hang Xu, Peter Hill, Jonathon Olsburgh, Gordon Beattie, Justine Korteweg, Nnenna Kanu, Martin Forster, Andrew Tutt, Ben Shum, Elias Pintus, Alison Cluroe, Matt Krebs, Patricia Roxburgh, Caroline Stirling, Selvaraju Veeriah, Olivia Curtis, Marc Robert de Massy, Emine Hatipoglu, Tom Lund, Kai-Keen Shiu, Tina Mackay, Pablo D. Becker, Faye Gishen, Massimo Loda, Aida Murra, Karin A. Oien, Joanne Webb, Jose Lopez, Sarah Sarker, Adrienne M. Flanagan, Ula Mahadeva, Ian Proctor, Ruby Stewart, John Le Quesne, Elaine Borg, Archana Fernando, Babu Naidu, Andrew Rowan, Abby Sharp, Mairead McKenzie, Ayse Akarca, Anthony J. Chalmers, James Spicer, Gary Middleton, Hollie Bancroft, Jo Dransfield, Nicos Fotiadis, Charlotte Ferris, Ron Sinclair, Mary Varia, Peter Van Loo, Lavinia Spain, Lena Karapagniotou, Nikki Hunter, Roberto Salgado, Sarah Vaughan, Chi-wah Lok, Karen Harrison-Phipps, Hema Verma, Jacqui Shaw, Rodelaine Wilson, Zoe Rhodes, Anna Green, Reena Khiroya, Miriam Mitchison, Ashish Chandra, Colin Watts, Peter Colloby, Uzma Asghar, Laura Farrelly, Tim O'Brien, Stephan Beck, Steve Hazell, Tanya Ahmad, Martin Collard, John Bridgewater, James D. Brenton, Sarah Rudman, Eleanor Carlyle, Andrew C. Kidd, Lizi Manzano, Sergio A. Quezada, Sioban Fraser, Allan Hackshaw, Nadia Yousaf, Samra Turajlic, Henning Walczak, David Nicol, Mariam Jamal-Hanjani, Sarah Howlett, Andrew Furness, Simranpreet Summan, Kevin G. Blyth, S. Baijal, Gert Attard, Marcos Duran Vasquez, Mita Afroza Akther, Karla Lingard, Ben Deakin, Ariana Huebner, and David G. Harrison

Subjects
Cancer Research, Receptors, Antigen, T-Cell, Biology, CD8-Positive T-Lymphocytes, Clinical Trials, Phase II as Topic, Antigen, Immunity, Exome Sequencing, medicine, Tumor Microenvironment, Humans, Prospective Studies, Spotlight, Mode of action, Receptor, Carcinoma, Renal Cell, Immune Checkpoint Inhibitors, Sequence Analysis, RNA, Gene Expression Profiling, T-cell receptor, Endogenous Retroviruses, Genomics, medicine.disease, Kidney Neoplasms, Clear cell renal cell carcinoma, Nivolumab, Oncology, Drug Resistance, Neoplasm, Cancer research, Tumor Escape, Single-Cell Analysis, CD8
Abstract

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Published
2021
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3. Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue

Author

Richard Marais, Andrew Furness, Thomas B.K. Watkins, Maise Al-Bakir, Dionysis Papadatos-Pastos, Maryam Razaq, Mairead McKenzie, Lisa Pickering, Peter Ellery, Jonathan Ledermann, Andrew V. Biankin, Richard J. Gilbertson, Peter Cockcroft, Mary Mangwende, Sophie Ward, Mary Falzon, Cristina Naceur-Lombardelli, Carlos Caldas, Karla Pearce, Jacqui Shaw, Salma Kadiri, Lars Dyrskjøt, Mark Linch, Daniel Burgess, Nelson Alexander, Christian H. Ottensmeier, Kevin G. Blyth, Lisa L. Gallegos, Rodelaine Wilson, Hayley Bridger, Fiona H Blackhall, Peter J. Parker, Charles Swanton, Allan Hackshaw, Gert Attard, Gordon Stamp, Dean A. Fennell, Debra H. Josephs, Andrew P. Robinson, Kim Edmonds, Tina Mackay, Mita Afroza Akther, Miriam Mitchison, Sam M. Janes, Giorgia Trevisan, Adrienne M. Flanagan, Alison Cluroe, Henning Walczak, Stuart Horswell, Lena Karapagniotou, Simon Tavaré, Sarah Sarker, Teresa Marafioti, Matt Krebs, Anna Green, Philippe Lamy, Reena Khiroya, Samantha M. Hill, Andrew Tutt, Ashish Chandra, Selvaraju Veeriah, Faye Gishen, Lisa Thompson, Sarah Vaughan, Stacey Stanislaw, Kevin Litchfield, Colin Watts, Caroline Dive, Zayd Tippu, Ron Sinclair, Merche Jimenez-Linan, Lavinia Spain, Lizi Manzano, Zoe Rhodes, Caroline Stirling, Elena Provenzano, Andrew Rowan, Katey S. S. Enfield, Vasiliki Michalarea, Nahid Sheikh, Antonia Toncheva, Charlotte Ferris, James Spicer, Kai-Keen Shiu, Aida Murra, Gerald Langman, Scott Thomas Colville Shepherd, Nicholas McGranahan, Fabio Gomes, Daniel Hochhauser, Hang Xu, Sergio A. Quezada, James Larkin, Siow Ming Lee, Chi-wah Lok, Massimo Loda, Gary Middleton, Hollie Bancroft, Jo Dransfield, David Moore, Jennifer Thomas, Rebecca C. Fitzgerald, Peter Colloby, Annika Fendler, Emma Beddowes, Ultan McDermott, Christopher Abbosh, Uzma Asghar, Martin Forster, John Le Quesne, Katherine F. Leith, Paddy Stone, Bernard Olisemeke, Bruce Tanchel, Laura Farrelly, Grant D. Stewart, Justine Korteweg, Sanjay Jogai, Nnenna Kanu, Desiree Schnidrig, Heidi Rosenbaum, Elaine Borg, Mat Carter, Anthony J. Chalmers, Andrew C. Kidd, Alexandre Harlé, Ula Mahadeva, Crispin T. Hiley, Fiona Byrne, Heather Shaw, Mariam Jamal-Hanjani, Karin A. Oien, Ian Proctor, Joanne Webb, Sioban Fraser, Sarah Howlett, Ruby Stewart, Peter Van Loo, Nadia Yousaf, Tanya Ahmad, Martin Collard, Sanjay Popat, James D. Brenton, Sarah Rudman, Lewis Au, David G. Harrison, Elias Pintus, Patricia Roxburgh, Olivia Curtis, Ben Deakin, Ariana Huebner, Debra Enting, Simranpreet Summan, S. Baijal, Iver Nordentoft, Carol Jones, Haixi Yan, Sebastian Brandner, Tariq Enver, Lara-Rose Iredale, Yvonne Summers, Babu Naidu, Abby Sharp, Stephen Hazell, Aoune Barhoumi, Emma Nye, Robert E. Hynds, Sharmistha Ghosh, Emilia L. Lim, Ben Shum, Nikki Hunter, John Bridgewater, Eleanor Carlyle, Stephan Beck, Nicolai Juul Birkbak, Steve Hazell, Samra Turajlic, Amy Kerr, Ian Tomlinson, Adrian Tookman, Litchfield, Kevin [0000-0002-3725-0914], Birkbak, Nicolai J [0000-0003-1613-9587], Nordentoft, Iver [0000-0003-4856-4086], Dyrskjøt, Lars [0000-0001-7061-9851], Apollo - University of Cambridge Repository, Division of genetics and epidemiology, The institute of cancer research [London], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), The Royal Marsden, University of Arizona, University of Western Ontario, Physic and Astronomy Department, University of Western Ontario (UWO), Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), Laboratoire d'Astrophysique de Marseille (LAM), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Aarhus University Hospital, Cancer Research UK Lung Cancer Centre of Excellence [Londres, Royaume-Uni], University College of London [London] (UCL), Comprehensive Cancer Center, UCL Cancer Institute [University College London], The Wellcome Trust Sanger Institute [Cambridge], Research Department of Pathology, Innovation North - Faculty of Information and Technology, Leeds Metropolitan University, Department of histopathology, University College Hospital, Mammalian Genetics Laboratory, Centre for Research on Adaptive Nanostructures and Nanodevices, Trinity College Dublin, Cancer Research UK London Research Institute, Guy's and St Thomas' Hospital [London], Breakthrough Breast Cancer Centre, London Institute of Cancer, Cancer Research UK Cambridge Research Institute and Department of Oncology, University of Cambridge, University of Cambridge [UK] (CAM), Cancer Division [Sydney, Australia] (The Kinghorn Cancer Centre), Garvan Institute of Medical Research [Sydney, Australia], Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, University of Leicester, Experimental Cancer Medicine Centre, University of Southampton-Faculty of Medicine, Moses, Wittemyer, Harrison and Woodruff, P.C., University of Oxford, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), and Garvan Institute of medical research

Subjects
0301 basic medicine, tumor sequencing, medicine.medical_specialty, Sampling protocol, tumor mutational burden, tumor sampling, Lung Neoplasms, molecular profiling, Biopsy, homogenization, Tissue sample, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Biomarkers, Tumor, Humans, Solid tumor, lcsh:QH301-705.5, Representative sampling, medicine.diagnostic_test, Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, Clonal structure, biomarkers, High-Throughput Nucleotide Sequencing, Tumor tissue, tumor hetereogeneity, Tumor Burden, 030104 developmental biology, lcsh:Biology (General), representative sampling, Urinary Bladder Neoplasms, Mutation, Radiology, 030217 neurology & neurosurgery
Abstract

International audience; Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias isinherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mmbiopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB butlow clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

Published
2020

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