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101. Supplementary Movie F from Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

Author

Dewhurst, Sally M., primary, McGranahan, Nicholas, primary, Burrell, Rebecca A., primary, Rowan, Andrew J., primary, Grönroos, Eva, primary, Endesfelder, David, primary, Joshi, Tejal, primary, Mouradov, Dmitri, primary, Gibbs, Peter, primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Szallasi, Zoltan, primary, Sieber, Oliver M., primary, and Swanton, Charles, primary

Published
2023
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102. Supplementary Figure 3 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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103. Supplementary Figure 2 from Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

Author

Dewhurst, Sally M., primary, McGranahan, Nicholas, primary, Burrell, Rebecca A., primary, Rowan, Andrew J., primary, Grönroos, Eva, primary, Endesfelder, David, primary, Joshi, Tejal, primary, Mouradov, Dmitri, primary, Gibbs, Peter, primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Szallasi, Zoltan, primary, Sieber, Oliver M., primary, and Swanton, Charles, primary

Published
2023
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104. Supplementary Figure 4 from Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

Author

Dewhurst, Sally M., primary, McGranahan, Nicholas, primary, Burrell, Rebecca A., primary, Rowan, Andrew J., primary, Grönroos, Eva, primary, Endesfelder, David, primary, Joshi, Tejal, primary, Mouradov, Dmitri, primary, Gibbs, Peter, primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Szallasi, Zoltan, primary, Sieber, Oliver M., primary, and Swanton, Charles, primary

Published
2023
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105. Supplementary Figure 6 from Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

Author

Dewhurst, Sally M., primary, McGranahan, Nicholas, primary, Burrell, Rebecca A., primary, Rowan, Andrew J., primary, Grönroos, Eva, primary, Endesfelder, David, primary, Joshi, Tejal, primary, Mouradov, Dmitri, primary, Gibbs, Peter, primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Szallasi, Zoltan, primary, Sieber, Oliver M., primary, and Swanton, Charles, primary

Published
2023
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106. Supplementary Figure 1 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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113. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

Author

McGranahan, Nicholas, Furness, Andrew J. S., Rosenthal, Rachel, Ramskov, Sofie, Lyngaa, Rikke, Saini, Sunil Kumar, Jamal-Hanjani, Mariam, Wilson, Gareth A., Birkbak, Nicolai J., Hiley, Crispin T., Watkins, Thomas B. K., Shafi, Seema, Murugaesu, Nirupa, Mitter, Richard, Akarca, Ayse U., Linares, Joseph, Marafioti, Teresa, Henry, Jake Y., Van Allen, Eliezer M., Miao, Diana, Schilling, Bastian, Schadendorf, Dirk, Garraway, Levi A., Makarov, Vladimir, Rizvi, Naiyer A., Snyder, Alexandra, Hellmann, Matthew D., Merghoub, Taha, Wolchok, Jedd D., Shukla, Sachet A., Wu, Catherine J., Peggs, Karl S., Chan, Timothy A., Hadrup, Sine R., Quezada, Sergio A., and Swanton, Charles

Published
2016

115. The evolution of lung cancer and impact of subclonal selection in TRACERx

Author

Frankell, Alexander M, Dietzen, Michelle, Al Bakir, Maise, Lim, Emilia L, Karasaki, Takahiro, Ward, Sophia, Veeriah, Selvaraju, Colliver, Emma, Huebner, Ariana, Bunkum, Abigail, Hill, Mark S, Grigoriadis, Kristiana, Moore, David A, Black, James RM, Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas BK, Naceur-Lombardelli, Cristina, Cook, Daniel E, Salgado, Roberto, Wilson, Gareth A, Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martinez-Ruiz, Carlos, Abbosh, Christopher, Nicholson, Andrew G, Le Quesne, John, Biswas, Dhruva, Rosenthal, Rachel, Puttick, Clare, Hessey, Sonya, Lee, Claudia, Prymas, Paulina, Toncheva, Antonia, Smith, Jon, Xing, Wei, Nicod, Jerome, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Blyth, Kevin G, Fennell, Dean A, Forster, Martin D, Lee, Siow Ming, Falzon, Mary, Hewish, Madeleine, Shackcloth, Michael J, Lim, Eric, Benafif, Sarah, Russell, Peter, Boleti, Ekaterini, Krebs, Matthew G, Lester, Jason F, Papadatos-Pastos, Dionysis, Ahmad, Tanya, Thakrar, Ricky M, Lawrence, David, Navani, Neal, Janes, Sam M, Dive, Caroline, Blackhall, Fiona H, Summers, Yvonne, Cave, Judith, Marafioti, Teresa, Herrero, Javier, Quezada, Sergio A, Peggs, Karl S, Schwarz, Roland F, Van Loo, Peter, Miedema, Daniel M, Birkbak, Nicolai J, Hiley, Crispin T, Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joa, Primrose, Lindsay, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Kaufmann, Tom L, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran L, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Rane, Jayant K, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Danson, Sarah, Robinson, Lily, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Lung Neoplasms, Treatment Outcome, DNA Copy Number Variations, Mutagenesis, Carcinoma, Non-Small-Cell Lung, Mutation, Smoking, Humans, Adenocarcinoma of Lung, Neoplasm Recurrence, Local, Phylogeny
Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. 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. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

117. Spatial Positioning of Immune Hotspots Reflects the Interplay between B and T Cells in Lung Squamous Cell Carcinoma

Author

Zhang, Hanyun, primary, AbdulJabbar, Khalid, additional, Moore, David A., additional, Akarca, Ayse, additional, Enfield, Katey S.S., additional, Jamal-Hanjani, Mariam, additional, Raza, Shan E. Ahmed, additional, Veeriah, Selvaraju, additional, Salgado, Roberto, additional, McGranahan, Nicholas, additional, Le Quesne, John, additional, Swanton, Charles, additional, Marafioti, Teresa, additional, and Yuan, Yinyin, additional

Published
2023
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120. Additional file 1 of ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

Author

Huebner, Ariana, Black, James R. M., Sarno, Francesca, Pazo, Roberto, Juez, Ignacio, Medina, Laura, Garcia-Carbonero, Rocio, Guillén, Carmen, Feliú, Jaime, Alonso, Carolina, Arenillas, Carlota, Moreno-Cárdenas, Ana Belén, Verdaguer, Helena, Macarulla, Teresa, Hidalgo, Manuel, McGranahan, Nicholas, and Toledo, Rodrigo A.

Abstract

Additional file 1. All supplementary figures.

Published
2023
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121. Late-stage metastatic melanoma emerges through a diversity of evolutionary pathways

Author

Spain, Lavinia, Coulton, Alexander, Lobon, Irene, Rowan, Andrew, Schnidrig, Desiree, Shepherd, Scott TC, Shum, Benjamin, Byrne, Fiona, Goicoechea, Maria, Piperni, Elisa, Au, Lewis, Edmonds, Kim, Carlyle, Eleanor, Hunter, Nikki, Renn, Alexandra, Messiou, Christina, Hughes, Peta, Nobbs, Jaime, Foijer, Floris, van den Bos, Hilda, Wardenaar, Rene, Spierings, Diana CJ, Spencer, Charlotte, Schmitt, Andreas M, Tippu, Zayd, Lingard, Karla, Grostate, Lauren, Peat, Kema, Kelly, Kayleigh, Sarker, Sarah, Vaughan, Sarah, Mangwende, Mary, Terry, Lauren, Kelly, Denise, Biano, Jennifer, Murra, Aida, Korteweg, Justine, Lewis, Charlotte, OFlaherty, Molly, Cattin, Anne-Laure, Emmerich, Max, Gerard, Camille L, Pallikonda, Husayn Ahmed, Lynch, Joanna, Mason, Robert, Rogiers, Aljosja, Xu, Hang, Huebner, Ariana, McGranahan, Nicholas, Al Bakir, Maise, Murai, Jun, Naceur-Lombardelli, Cristina, Borg, Elaine, Mitchison, Miriam, Moore, David A, Falzon, Mary, Proctor, Ian, Stamp, Gordon WH, Nye, Emma L, Young, Kate, Furness, Andrew JS, Pickering, Lisa, Stewart, Ruby, Mahadeva, Ula, Green, Anna, Larkin, James, Litchfield, Kevin, Swanton, Charles, Jamal-Hanjani, Mariam, Consortium, The PEACE, and Turajlic, Samra

Subjects
Chemical Biology & High Throughput, Signalling & Oncogenes, Human Biology & Physiology, Ecology,Evolution & Ethology, Genome Integrity & Repair, Tumour Biology, Genetics & Genomics, Computational & Systems Biology
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 intra-patient metastatic melanoma dataset assembled to date as part of the PEACE research autopsy programme, including 222 exome, 493 panel-sequenced, 161 RNA-seq, 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 non-responders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one of the patients. 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.

Published
2023
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122. Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Author

Ng, Kevin W, Boumelha, Jesse, Enfield, Katey SS, Almagro, Jorge, Cha, Hongui, Pich, Oriol, Karasaki, Takahiro, Moore, David A, Salgado, Roberto, Sivakumar, Monica, Young, George, Molina-Arcas, Miriam, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott TC, Martínez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Watkins, Thomas BK, Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia, Frankell, Alexander M, Al Bakir, Maise, Lim, Emilia L, Hill, Mark S, Wilson, Gareth A, Cook, Daniel E, Birkbak, Nicolai J, Behrens, Axel, Yousaf, Nadia, Popat, Sanjay, Hackshaw, Allan, Consortium, TRACERx, Consortium, CAPTURE, Hiley, Crispin T, Litchfield, Kevin, McGranahan, Nicholas, Jamal-Hanjani, Mariam, Larkin, James, Lee, Se-Hoon, Turajlic, Samra, Swanton, Charles, Downward, Julian, and Kassiotis, George

Subjects
Model organisms, Lung Neoplasms, Immunology, Gene Expression, Adenocarcinoma of Lung, Infectious Disease, Antibodies, Cohort Studies, Mice, Signalling & Oncogenes, Ecology,Evolution & Ethology, Carcinoma, Non-Small-Cell Lung, Tumor Microenvironment, Animals, Humans, Lung, Computational & Systems Biology, Chemical Biology & High Throughput, B-Lymphocytes, Human Biology & Physiology, Stem Cells, FOS: Clinical medicine, Endogenous Retroviruses, Genome Integrity & Repair, Cell Biology, Tumour Biology, Disease Models, Animal, Cell Cycle & Chromosomes, Immunotherapy, Genetics & Genomics
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. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023
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123. The evolution of non-small cell lung cancer metastases in TRACERx

Author

Al Bakir, Maise, Huebner, Ariana, Martínez-Ruiz, Carlos, Grigoriadis, Kristiana, Watkins, Thomas BK, Pich, Oriol, Moore, David A, Veeriah, Selvaraju, Ward, Sophia, Laycock, Joanne, Johnson, Diana, Rowan, Andrew, Razaq, Maryam, Akther, Mita, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Hessey, Sonya, Dietzen, Michelle, Colliver, Emma, Frankell, Alexander M, Bunkum, Abigail, Lim, Emilia L, Karasaki, Takahiro, Abbosh, Christopher, Hiley, Crispin T, Hill, Mark S, Cook, Daniel E, Wilson, Gareth A, Salgado, Roberto, Nye, Emma, Stone, Richard Kevin, Fennell, Dean A, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Summers, Yvonne, Lindsay, Colin R, Blackhall, Fiona H, Cave, Judith, Blyth, Kevin G, Nair, Arjun, Ahmed, Asia, Taylor, Magali N, Procter, Alexander James, Falzon, Mary, Lawrence, David, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Papadatos-Pastos, Dionysis, Forster, Martin D, Lee, Siow Ming, Ahmad, Tanya, Quezada, Sergio A, Peggs, Karl S, Van Loo, Peter, Dive, Caroline, Hackshaw, Allan, Birkbak, Nicolai J, Zaccaria, Simone, Consortium, TRACERx, Jamal-Hanjani, Mariam, McGranahan, Nicholas, and Swanton, Charles

Subjects
Model organisms, Chemical Biology & High Throughput, Human Biology & Physiology, Stem Cells, FOS: Clinical medicine, Genome Integrity & Repair, Immunology, Cell Biology, Tumour Biology, Signalling & Oncogenes, Ecology,Evolution & Ethology, Cell Cycle & Chromosomes, Genetics & Genomics, Computational & Systems Biology
Abstract

Metastatic disease is responsible for the majority of cancer-related deaths1. 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.

Published
2023
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124. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Author

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

Subjects
Lung cancer -- Genetic aspects -- Development and progression, DNA sequencing -- Methods, Phylogeny -- Observations, Cancer metastasis -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies., Author(s): Christopher Abbosh [1]; Nicolai J. Birkbak [1, 2]; Gareth A. Wilson [1, 2]; Mariam Jamal-Hanjani [1]; Tudor Constantin [3]; Raheleh Salari [3]; John Le Quesne [4]; David A. Moore [...]

Published
2017
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129. Genome instability underlies an augmented DNA damage response in familial and sporadic ALS human iPSC-derived motor neurons

Author

Ziff, Oliver, primary, Neeves, Jacob, additional, Mitchell, Jamie, additional, Tyzack, Guilia, additional, Ruiz, Carlos, additional, McGranahan, Nicholas, additional, Luisier, Raphaelle, additional, Chakrabarti, Anob, additional, Boulton, Simon, additional, Kelly, Gavin, additional, Humphrey, Jack, additional, and Patani, Rickie, additional

Published
2022
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130. Non-Small-Cell Lung Cancer Promotion by Air Pollutants

Author

Swanton, Charles, primary, Hill, William, additional, Lim, Emilia, additional, Lee, Claudia, additional, Weeden, Clare, additional, Augustine, Marcellus, additional, Chen, Kezhong, additional, Kuan, Feng-Che, additional, Marongiu, Fabio, additional, Evans, Edward, additional, Moore, David, additional, Rodrigues, Felipe, additional, Maldegem, Febe van, additional, Boumelha, Jesse, additional, Veeriah, Selvaraju, additional, Rowan, Andrew, additional, Naceur-Lombardelli, Cristina, additional, Karasaki, Takahiro, additional, Sivakumar, Monica, additional, Caswell, Deborah, additional, Nagano, Ai, additional, Ryu, Min Hyung, additional, Huff, Ryan, additional, Li, Shijia, additional, Magness, Alastair, additional, Suarez-Bonnet, Alejandro, additional, Priestnall, Simon, additional, Lüchtenborg, Margreet, additional, Lavelle, Katrina, additional, Pethick, Joanna, additional, Hardy, Steven, additional, McRonald, Fiona, additional, Lin, Meng-Hung, additional, Troccoli, Clara, additional, Ghosh, Moumita, additional, Miller, York, additional, Merrick, Daniel, additional, Keith, Robert, additional, Bakir, Maise Al, additional, Bailey, Chris, additional, Saal, Lao, additional, Chen, Yilun, additional, George, Anthony, additional, Abbosh, Chris, additional, Kanu, Nnennaya, additional, Lee, Se-Hoon, additional, McGranahan, Nicholas, additional, Berg, Chistine, additional, Grönroos, Eva, additional, Downward, Julian, additional, Jacks, Tyler, additional, Carlsten, Christopher, additional, Malanchi, Ilaria, additional, Hackshaw, Allan, additional, Litchfield, Kevin, additional, Jamal-Hanjani, Mariam, additional, and DeGregori, James, additional

Published
2022
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131. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution

Author

de Bruin, Elza C., McGranahan, Nicholas, Mitter, Richard, Salm, Max, Wedge, David C., Yates, Lucy, Jamal-Hanjani, Mariam, Shafi, Seema, Murugaesu, Nirupa, Rowan, Andrew J., Grönroos, Eva, Muhammad, Madiha A., Horswell, Stuart, Gerlinger, Marco, Varela, Ignacio, Jones, David, Marshall, John, Voet, Thierry, Van Loo, Peter, Rassl, Doris M., Rintoul, Robert C., Janes, Sam M., Lee, Siow-Ming, Forster, Martin, Ahmad, Tanya, Lawrence, David, Falzon, Mary, Capitanio, Arrigo, Harkins, Timothy T., Lee, Clarence C., Tom, Warren, Teefe, Enock, Chen, Shann-Ching, Begum, Sharmin, Rabinowitz, Adam, Phillimore, Benjamin, Spencer-Dene, Bradley, Stamp, Gordon, Szallasi, Zoltan, Matthews, Nik, Stewart, Aengus, Campbell, Peter, and Swanton, Charles

Published
2014

135. Abstract 204: Notch2NL is a novel regulator of radiation sensitivity in non-small cell lung cancer and a positive regulator of MYC activity

Author

Summan, Simranpreet Kaur, primary, Chow, Barbara, additional, Millar, Rhona, additional, Chew, Su Kit, additional, East, Philip, additional, Hynds, Robert, additional, Ruiz, Carlos Martinez, additional, Gronroos, Eva, additional, Jamal-Hanjani, Mariam, additional, Litchfield, Kevin, additional, McGranahan, Nicholas, additional, Kanu, Nnennaya, additional, Swanton, Charles, additional, and Hiley, Crispin Thomas, additional

Published
2022
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137. Abstract 2197: Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance

Author

Mayekar, Manasi, primary, Caswell, Deborah, additional, Vokes, Natalie, additional, Law, Emily K., additional, Wu, Wei, additional, Hill, William, additional, Gronroos, Eva, additional, Rowan, Andrew, additional, Bakir, Maise Al, additional, Weeden, Clare, additional, McCoach, Caroline E., additional, Blakely, Collin M., additional, Temiz, Nuri Alpay, additional, Nagano, Ai, additional, Kerr, Daniel L., additional, Rotow, Julia K., additional, Pich, Oriol, additional, Haderk, Franziska, additional, Dietzen, Michelle, additional, Ruiz, Carlos Martinez, additional, Almeida, Bruna, additional, Cech, Lauren, additional, Gini, Beatrice, additional, Przewrocka, Joanna, additional, Moore, Chris, additional, Murillo, Miguel, additional, Bakker, Bjorn, additional, Rule, Brandon, additional, Durfee, Cameron, additional, Nanj, Shigeki, additional, Tan, Lisa, additional, Larson, Lindsay K., additional, Argyris, Prokopios P., additional, Brown, William L., additional, Yu, Johnny, additional, Gomez, Carlos, additional, Gui, Philippe, additional, Vogel, Rachel I., additional, Yu, Elizabeth A., additional, Thomas, Nicholas J., additional, Venkatesan, Subramanian, additional, Hobor, Sebastijan, additional, Chew, Su Kit, additional, McGranahan, Nicholas, additional, Kanu, Nnennaya, additional, Van Allen, Eliezer M., additional, Downward, Julian, additional, Harris, Reuben S., additional, Bivona, Trever, additional, and Swanton, Charles, additional

Published
2022
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138. Abstract 645: Heterogeneity of immunotherapy biomarkers in the TRACERx non-small cell lung cancer multi-region lung cancer cohort study

Author

Hiley, Crispin T., primary, Litchfield, Kevin, additional, Pich, Oriol, additional, Moore, David, additional, Naceur-Lombardelli, Cristina, additional, Veeriah, Selvaraju, additional, Bakir, Maise Al, additional, Summan, Simranpreet, additional, Grigoriadis, Kristiana, additional, Ruiz, Carlos Martinez, additional, Puttick, Clare, additional, Enfield, Katey, additional, Ward, Sophia, additional, Frankell, Alexander, additional, Biswas, Dhruva, additional, Rosenthal, Rachel, additional, Birkbak, Nicolai J., additional, Jamal-Hanjani, Mariam, additional, McGranahan, Nicholas, additional, Swanton, Charles, additional, and Consortium, TRACERx, additional

Published
2022
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139. Abstract 5636: V-delta-1 T cells are resident in the human lung and associate with survival in patients with non-small cell lung cancer in the TRACERx Study

Author

Wu, Yin, primary, Biswas, Dhruva, additional, Usaite, Ieva, additional, Mihaela, Angelova, additional, Boeing, Stefan, additional, Karasaki, Takahiro, additional, Veeriah, Selvaraju, additional, Czyzewska-Khan, Justyna, additional, Reading, James, additional, Georgiou, Andrew, additional, Al-Bakir, Maise, additional, McGranahan, Nicholas, additional, Jamal-Hanjani, Mariam, additional, Hackshaw, Allan, additional, Consortium, TRACERx, additional, Quezada, Sergio, additional, Hayday, Adrian, additional, and Swanton, Charles, additional

Published
2022
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140. Abstract 1394: Pervasive allele specific transcriptional repression of the class I and II HLA genes in TRACERx non-small cell lung cancer

Author

Puttick, Clare, primary, Pich, Oriol, additional, Leung, Michelle, additional, Martinez-Ruiz, Carlos, additional, Bentham, Robert, additional, Rosenthal, Rachel, additional, Hessey, Sonya, additional, Black, James R., additional, Lim, Emilia L., additional, Enfield, Katey, additional, Colliver, Emma, additional, Dijkstra, Krijn, additional, Hiley, Crispin T., additional, Karasaki, Takahiro, additional, Huebner, Ariana, additional, Bakir, Maise Al, additional, Watkins, Thomas B., additional, Frankell, Alexander M., additional, Zaccaria, Simone, additional, Jamal-Hanjani, Mariam, additional, McGranahan, Nicholas, additional, and Swanton, Charles, additional

Published
2022
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141. Abstract 3096: Multi-region patient-derived xenograft models from non-small cell lung cancer patients enrolled in lung TRACERx

Author

Hynds, Robert E., primary, Pearce, David R., additional, Akarca, Ayse U., additional, Ward, Sophia, additional, Huebner, Ariana, additional, Pich, Oriol, additional, Wilson, Gareth A., additional, Gowers, Kate H., additional, Towns, Rebecca, additional, Aissa, Assma Ben, additional, Veeriah, Selvaraju, additional, Quezada, Sergio A., additional, Jamal-Hanjani, Mariam, additional, Janes, Sam M., additional, McGranahan, Nicholas, additional, Moore, David A., additional, Marafioti, Teresa, additional, and Swanton, Charles, additional

Published
2022
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142. Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive transfer with tumor-infiltrating lymphocytes in melanoma

Author

Kristensen, Nikolaj Pagh, Heeke, Christina, Tvingsholm, Siri A., Borch, Annie, Draghi, Arianna, Crowther, Michael D., Carri, Ibel, Munk, Kamilla K., Holm, Jeppe Sejerø, Bjerregaard, Anne-Mette, Bentzen, Amalie Kai, Marquard, Andrea M., Szallasi, Zoltan, McGranahan, Nicholas, Andersen, Rikke, Nielsen, Morten, Jönsson, Göran B, Donia, Marco, Svane, Inge Marie, Hadrup, Sine Reker, Kristensen, Nikolaj Pagh, Heeke, Christina, Tvingsholm, Siri A., Borch, Annie, Draghi, Arianna, Crowther, Michael D., Carri, Ibel, Munk, Kamilla K., Holm, Jeppe Sejerø, Bjerregaard, Anne-Mette, Bentzen, Amalie Kai, Marquard, Andrea M., Szallasi, Zoltan, McGranahan, Nicholas, Andersen, Rikke, Nielsen, Morten, Jönsson, Göran B, Donia, Marco, Svane, Inge Marie, and Hadrup, Sine Reker

Abstract

BACKGROUND. Neoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with Tumor-Infiltrating Lymphocytes (TILs). Yet, how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined. METHODS. Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic melanoma patients who received ACT. RESULTS. We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product. CONCLUTIONS. These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma, and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells.

Published
2022

143. ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA.

Author

Huebner, Ariana, Black, James R. M., Sarno, Francesca, Pazo, Roberto, Juez, Ignacio, Medina, Laura, Garcia-Carbonero, Rocio, Guillén, Carmen, Feliú, Jaime, Alonso, Carolina, Arenillas, Carlota, Moreno-Cárdenas, Ana Belén, Verdaguer, Helena, Macarulla, Teresa, Hidalgo, Manuel, McGranahan, Nicholas, and Toledo, Rodrigo A.

Subjects
CIRCULATING tumor DNA, PANCREATIC cancer, CELL-free DNA, SOMATIC mutation, KARYOTYPES, SOMATIC embryogenesis
Abstract

Background: Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods: To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results: SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions: This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy. [ABSTRACT FROM AUTHOR]

Published
2023
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144. Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology.

Author

Ziff, Oliver J., Neeves, Jacob, Mitchell, Jamie, Tyzack, Giulia, Martinez-Ruiz, Carlos, Luisier, Raphaelle, Chakrabarti, Anob M., McGranahan, Nicholas, Litchfield, Kevin, Boulton, Simon J., Al-Chalabi, Ammar, Kelly, Gavin, Humphrey, Jack, and Patani, Rickie

Subjects
AMYOTROPHIC lateral sclerosis, DNA repair, SOMATIC mutation, MOTOR neurons, SPINAL cord, GENE fusion
Abstract

Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response. The causes of ALS remain unclear with many proposed pathomechanisms. Here, the authors integrate iPSC-derived motor neuron and post-mortem datasets and identify a heightened DNA damage response accompanied by accumulation of somatic mutations in ALS. [ABSTRACT FROM AUTHOR]

Published
2023
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148. Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay

Author

Orlando, Francesco, Romanel, Alessandro, Trujillo, Blanca, Sigouros, Michael, Wetterskog, Daniel, Quaini, Orsetta, Leone, Gianmarco, Xiang, Jenny Z, Wingate, Anna, Tagawa, Scott, Jayaram, Anuradha, Linch, Mark, Swanton, Charles, Jamal-Hanjani, Mariam, Abbosh, Chris, Zaccaria, Simone, Hessey, Sonya, Shiu, Kai-Keen, Bridgewater, John, Hochhauser, Daniel, Forster, Martin, Lee, Siow-Ming, Ahmad, Tanya, Papadatos-Pastos, Dionysis, Janes, Sam, Van Loo, Peter, Enfield, Katey, McGranahan, Nicholas, Huebner, Ariana, Quezada, Sergio, Beck, Stephan, Parker, Peter, Enver, Tariq, Hynds, Robert E, Dijkstra, Krijn, Pearce, David R, Falzon, Mary, Proctor, Ian, Sinclair, Ron, Lok, Chi-wah, Rhodes, Zoe, Moore, David, Marafioti, Teresa, Mitchison, Miriam, Ellery, Peter, Sivakumar, Monica, Brandner, Sebastian, Rowan, Andrew, Hiley, Crispin, Veeriah, Selvaraju, Shaw, Heather, Attard, Gert, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Prymas, Paulina, Watkins, Tom, Bailey, Chris, Ruiz, Carlos Martinez, Litchfield, Kevin, Al-Bakir, Maise, Kanu, Nnenna, Ward, Sophie, Lim, Emilia, Reading, James, Chain, Benny, Alba, Blanca Trujillo, Akay, Melek, Flanagan, Adrienne, Biswas, Dhruva, Pich, Oriol, Dietzen, Michelle, Puttick, Clare, Colliver, Emma, Magness, Alistair, Angelova, Mihaela, Black, James, Lucas, Olivia, Hill, William, Liu, Wing-Kin, Frankell, Alexander, Magno, Neil, Athanasopoulou, Foteini, Wilson, Gareth, Rosenthal, Rachel, Salgado, Roberto, Lee, Claudia, Grigoriadis, Kristiana, Al-Sawaf, Othman, Karasaki, Takahiro, Bunkum, Abigail, Noorani, Imran, Benafif, Sarah, Barbe, Vittorio, Bola, Supreet, Vainauskas, Osvaldas, Hasan, Mahedi, Lise, Stefano, Leone, GianMarco, Alifrangis, Constantine, McGovern, Ursula, Thol, Kerstin, Gamble, Samuel, Ung, Seng Kuong, Sahwangarrom, Teerapon, Marin, Claudia Peinador, Wong, Sophia, Pawlik, Piotr, Gishen, Faye, Tookman, Adrian, Stone, Paddy, Stirling, Caroline, Turajlic, Samra, Larkin, James, Pickering, Lisa, Furness, Andrew, Young, Kate, Drake, Will, Edmonds, Kim, Hunter, Nikki, Mangwende, Mary, Pearce, Karla, Grostate, Lauren, Au, Lewis, Spain, Lavinia, Shepherd, Scott, Yan, Haixi, Shum, Ben, Tippu, Zayd, Hanley, Brian, Spencer, Charlotte, Emmerich, Max, Gerard, Camille, Schmitt, Andreas Michael, Del Rosario, Lyra, Carlyle, Eleanor, Lewis, Charlotte, Holt, Lucy, Lucanas, Analyn, O'Flaherty, Molly, Hazell, Steve, Mudhar, Hardeep, Messiou, Christina, Latifoltojar, Arash, Fendler, Annika, Byrne, Fiona, Pallinkonda, Husayn, Lobon, Irene, Coulton, Alex, Cattin, Anne Laure, Deng, Daqi, Feng, Geoffrey Hugang, Rowan, Andew, Yousaf, Nadia, Popat, Sanjay, Curtis, Olivia, Milner-Watts, Charlotte, Stamp, Gordon, Nye, Emma, Murra, Aida, Korteweg, Justine, Kelly, Denise, Terry, Lauren, Biano, Jennifer, Peat, Kema, Kelly, Kayleigh, Hill, Peter, Josephs, Debra, Irshad, Sheeba, Chandra, Ashish, Spicer, James, Mahadeva, Ula, Green, Anna, Stewart, Ruby, Iredale, Lara-Rose, Mackay, Tina, Deakin, Ben, Enting, Debra, Rudman, Sarah, Ghosh, Sharmistha, Karapagniotou, Lena, Pintus, Elias, Tutt, Andrew, Howlett, Sarah, Michalarea, Vasiliki, Brenton, James, Caldas, Carlos, Fitzgerald, Rebecca, Jimenez-Linan, Merche, Provenzano, Elena, Cluroe, Alison, Paterson, Anna, Aitken, Sarah, Allinson, Kieren, Stewart, Grant, McDermott, Ultan, Beddowes, Emma, Maughan, Tim, Ansorge, Olaf, Campbell, Peter, Roxburgh, Patricia, Fraser, Sioban, Kidd, Andrew, Blyth, Kevin, Le Quesne, John, Krebs, Matthew, Blackhall, Fiona, Summers, Yvonne, Oliveira, Pedro, Ortega-Franco, Ana, Dive, Caroline, Gomes, Fabio, Carter, Mat, Dransfield, Jo, Thomas, Anne, Fennell, Dean, Shaw, Jacqui, Naidu, Babu, Baijal, Shobhit, Tanchel, Bruce, Langman, Gerald, Robinson, Andrew, Collard, Martin, Cockcroft, Peter, Ferris, Charlotte, Bancroft, Hollie, Kerr, Amy, Middleton, Gary, Webb, Joanne, Kadiri, Salma, Colloby, Peter, Olisemeke, Bernard, Wilson, Rodelaine, Tomlinson, Ian, McNeish, Iain, Jogai, Sanjay, Holden, Samantha, Fernandes, Tania, Hampton, Blanche, McKenzie, Mairead, Hackshaw, Allan, Sharp, Abby, Chan, Kitty, Farrelly, Laura, Bridger, Hayley, Leslie, Rachel, Consortium, PEACE, Rubin, Mark A, Wyatt, Alexander W, Beltran, Himisha, Attard, Gerhardt, and Demichelis, Francesca

Subjects
Chemical Biology & High Throughput, Signalling & Oncogenes, Human Biology & Physiology, Ecology,Evolution & Ethology, Genome Integrity & Repair, Tumour Biology, Genetics & Genomics, Computational & Systems Biology
Abstract

Sequencing of cell-free DNA (cfDNA) in cancer patients’ plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with

Published
2022
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149. TUMOR IMMUNOLOGY: Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

Author

McGranahan, Nicholas, Furness, Andrew J.S., Rosenthal, Rachel, Ramskov, Sofie, Lyngaa, Rikke, Saini, Sunil Kumar, Jamal-Hanjani, Mariam, Wilson, Gareth A., Birkbak, Nicolai J., Hiley, Crispin T., Watkins, Thomas B.K., Shafi, Seema, Murugaesu, Nirupa, Mitter, Richard, Akarca, Ayse U., Linares, Joseph, Marafioti, Teresa, Henry, Jake Y., Van Allen, Eliezer M., Miao, Diana, Schilling, Bastian, Schadendorf, Dirk, Garraway, Levi A., Makarov, Vladimir, Rizvi, Naiyer A., Snyder, Alexandra, Hellmann, Matthew D., Merghoub, Taha, Wolchok, Jedd D., Shukla, Sachet A., Wu, Catherine J., Peggs, Karl S., Chan, Timothy A., Hadrup, Sine R., Quezada, Sergio A., and Swanton, Charles

Published
2016
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150. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Author

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

Published
2021
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