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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. Data from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Author

Samra Turajlic, Mariam Jamal-Hanjani, Charles Swanton, Kevin Litchfield, James Larkin, Anna Green, Ula Mahadeva, Ruby Stewart, Lisa Pickering, Andrew J.S. Furness, Kate Young, Emma L. Nye, Gordon W.H. Stamp, Ian Proctor, Mary Falzon, David A. Moore, Miriam Mitchison, Elaine Borg, Cristina Naceur-Lombardelli, Jun Murai, Maise Al Bakir, Nicholas McGranahan, Ariana Huebner, Hang Xu, Aljosja Rogiers, Robert Mason, Joanna Lynch, Husayn Ahmed Pallikonda, Camille L. Gerard, Max Emmerich, Anne-Laure Cattin, Molly O'Flaherty, Charlotte Lewis, Justine Korteweg, Aida Murra, Jennifer Biano, Denise Kelly, Lauren Terry, Mary Mangwende, Sarah Vaughan, Sarah Sarker, Kayleigh Kelly, Kema Peat, Lauren Grostate, Karla Lingard, Zayd Tippu, Andreas M. Schmitt, Charlotte Spencer, Diana C.J. Spierings, Rene Wardenaar, Hilda van den Bos, Floris Foijer, Jaime Nobbs, Peta Hughes, Christina Messiou, Alexandra Renn, Nikki Hunter, Eleanor Carlyle, Kim Edmonds, Lewis Au, Elisa Piperni, Maria Goicoechea, Fiona Byrne, Benjamin Shum, Scott T.C. Shepherd, Desiree Schnidrig, Andrew Rowan, Irene Lobon, Alexander Coulton, and Lavinia Spain

Abstract

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.Significance:Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.

Published
2023
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3. Supplementary Figures S1-S25 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Author

Samra Turajlic, Mariam Jamal-Hanjani, Charles Swanton, Kevin Litchfield, James Larkin, Anna Green, Ula Mahadeva, Ruby Stewart, Lisa Pickering, Andrew J.S. Furness, Kate Young, Emma L. Nye, Gordon W.H. Stamp, Ian Proctor, Mary Falzon, David A. Moore, Miriam Mitchison, Elaine Borg, Cristina Naceur-Lombardelli, Jun Murai, Maise Al Bakir, Nicholas McGranahan, Ariana Huebner, Hang Xu, Aljosja Rogiers, Robert Mason, Joanna Lynch, Husayn Ahmed Pallikonda, Camille L. Gerard, Max Emmerich, Anne-Laure Cattin, Molly O'Flaherty, Charlotte Lewis, Justine Korteweg, Aida Murra, Jennifer Biano, Denise Kelly, Lauren Terry, Mary Mangwende, Sarah Vaughan, Sarah Sarker, Kayleigh Kelly, Kema Peat, Lauren Grostate, Karla Lingard, Zayd Tippu, Andreas M. Schmitt, Charlotte Spencer, Diana C.J. Spierings, Rene Wardenaar, Hilda van den Bos, Floris Foijer, Jaime Nobbs, Peta Hughes, Christina Messiou, Alexandra Renn, Nikki Hunter, Eleanor Carlyle, Kim Edmonds, Lewis Au, Elisa Piperni, Maria Goicoechea, Fiona Byrne, Benjamin Shum, Scott T.C. Shepherd, Desiree Schnidrig, Andrew Rowan, Irene Lobon, Alexander Coulton, and Lavinia Spain

Abstract

Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number sample trees. Supplementary figure 6: MEDICC tree of all exome samples demonstrating that samples cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes, with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all samples. Supplementary figure 13: Number of samples per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for samples with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk samples from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of samples for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of samples for which RNA-seq was performed faceted by tissue site.

Published
2023
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4. Supplementary Tables S1-S8 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Author

Samra Turajlic, Mariam Jamal-Hanjani, Charles Swanton, Kevin Litchfield, James Larkin, Anna Green, Ula Mahadeva, Ruby Stewart, Lisa Pickering, Andrew J.S. Furness, Kate Young, Emma L. Nye, Gordon W.H. Stamp, Ian Proctor, Mary Falzon, David A. Moore, Miriam Mitchison, Elaine Borg, Cristina Naceur-Lombardelli, Jun Murai, Maise Al Bakir, Nicholas McGranahan, Ariana Huebner, Hang Xu, Aljosja Rogiers, Robert Mason, Joanna Lynch, Husayn Ahmed Pallikonda, Camille L. Gerard, Max Emmerich, Anne-Laure Cattin, Molly O'Flaherty, Charlotte Lewis, Justine Korteweg, Aida Murra, Jennifer Biano, Denise Kelly, Lauren Terry, Mary Mangwende, Sarah Vaughan, Sarah Sarker, Kayleigh Kelly, Kema Peat, Lauren Grostate, Karla Lingard, Zayd Tippu, Andreas M. Schmitt, Charlotte Spencer, Diana C.J. Spierings, Rene Wardenaar, Hilda van den Bos, Floris Foijer, Jaime Nobbs, Peta Hughes, Christina Messiou, Alexandra Renn, Nikki Hunter, Eleanor Carlyle, Kim Edmonds, Lewis Au, Elisa Piperni, Maria Goicoechea, Fiona Byrne, Benjamin Shum, Scott T.C. Shepherd, Desiree Schnidrig, Andrew Rowan, Irene Lobon, Alexander Coulton, and Lavinia Spain

Abstract

S. Table 1: List of PEACE Consortium members. S. Table 2: Sample database used for the study for Panel, Exome and RNASeq samples. S. Table 3: Overview of lines of treatment given to each patient. S. Table 4: Lesions and patients included in the lesion-level response to ICI analysis. S. Table 5: Hallmark genesets significantly upregulated in normal tissue vs tumor tissue. Table shows p-values for tissue type, purity; T value for tissue type, purity; q-value for tissue type, purity (FDR corrected). S. Table 6: Hallmark genesets significantly upregulated in tumor tissue vs normal tissue. Table shows p-values for tissue type, purity; T value for tissue type, purity; q-value for tissue type, purity (FDR corrected). S. Table 7: Genes included in the target panel. S. Table 8: Tree topology comparisons between manually constructed trees and pairtree-constructed trees.

Published
2023
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5. 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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6. Abstract A012: Advanced melanoma exhibits a diversity of evolutionary routes to lethality

Author

Alexander Coulton, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum, Fiona Byrne, Lewis Au, Kim Edmonds, Ellie Carlyle, Alexandra Renn, Christina Messiou, Charlotte Spencer, Andreas M. Schmidt, Zayd Tippu, Aljosja Rogiers, Max Emmerich, Camille Gerard, Husayn Pallikonda, Cristina Naceur-Lombardelli, Floris Foijer, Hilda van den Bos, René Wardenaar, Diana Spierings, Kate Young, Lisa Pickering, Andrew Furness, Elaine Borg, Miriam Mitchison, David Moore, Mary Falzon, Ian Proctor, Ruby Stewart, Ula Mahadeva, Anna Green, James Larkin, Charles Swanton, Mariam Jamal-Hanjani, Kevin Litchfield, and Samra Turajlic

Subjects
Cancer Research, Oncology
Abstract

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR002) of the Conference Proceedings. Citation Format: Alexander Coulton, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum, Fiona Byrne, Lewis Au, Kim Edmonds, Ellie Carlyle, Alexandra Renn, Christina Messiou, Charlotte Spencer, Andreas M. Schmidt, Zayd Tippu, Aljosja Rogiers, Max Emmerich, Camille Gerard, Husayn Pallikonda, Cristina Naceur-Lombardelli, Floris Foijer, Hilda van den Bos, René Wardenaar, Diana Spierings, Kate Young, Lisa Pickering, Andrew Furness, Elaine Borg, Miriam Mitchison, David Moore, Mary Falzon, Ian Proctor, Ruby Stewart, Ula Mahadeva, Anna Green, James Larkin, Charles Swanton, Mariam Jamal-Hanjani, Kevin Litchfield, Samra Turajlic. Advanced melanoma exhibits a diversity of evolutionary routes to lethality [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A012.

Published
2022
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