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2. Ages of the Avant-Garde

Author

Marranca, Bonnie, Monk, Meredith, Foreman, Richard, Schneemann, Carolee, Fornes, Maria Irene, Jowitt, Deborah, Hay, Deborah, Rosenthal, Rachel, Johnston, Jill, Bernard, Kenneth, Rainer, Yvonne, van Itallie, Jean-Claude, Higgins, Dick, Kostelanetz, Richard, Malina, Judith, Aaron, Joyce, Blau, Herbert, Halprin, Anna, Hammer, Barbara, Drexler, Rosalyn, Owens, Rochelle, and Kaprow, Allan

Published
2018

3. Author Correction: 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 R. M., Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas B. K., Naceur-Lombardelli, Cristina, Cook, Daniel E., Salgado, Roberto, Wilson, Gareth A., Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martínez-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, Daniël M., Birkbak, Nicolai J., Hiley, Crispin T., Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, and Swanton, Charles

Published
2024
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6. 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 R. M., Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas B. K., Naceur-Lombardelli, Cristina, Cook, Daniel E., Salgado, Roberto, Wilson, Gareth A., Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martínez-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, Daniël M., Birkbak, Nicolai J., Hiley, Crispin T., Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, and Swanton, Charles

Published
2023
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7. Genomic–transcriptomic evolution in lung cancer and metastasis

Author

Martínez-Ruiz, Carlos, Black, James R. M., Puttick, Clare, Hill, Mark S., Demeulemeester, Jonas, Larose Cadieux, Elizabeth, Thol, Kerstin, Jones, Thomas P., Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Prymas, Paulina, Rowan, Andrew, Ward, Sophia, Cubitt, Laura, Athanasopoulou, Foteini, Pich, Oriol, Karasaki, Takahiro, Moore, David A., Salgado, Roberto, Colliver, Emma, Castignani, Carla, Dietzen, Michelle, Huebner, Ariana, Al Bakir, Maise, Tanić, Miljana, Watkins, Thomas B. K., Lim, Emilia L., Al-Rashed, Ali M., Lang, Danny, Clements, James, Cook, Daniel E., Rosenthal, Rachel, Wilson, Gareth A., Frankell, Alexander M., de Carné Trécesson, Sophie, East, Philip, Kanu, Nnennaya, Litchfield, Kevin, Birkbak, Nicolai J., Hackshaw, Allan, Beck, Stephan, Van Loo, Peter, Jamal-Hanjani, Mariam, Swanton, Charles, and McGranahan, Nicholas

Published
2023
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11. Pervasive chromosomal instability and karyotype order in tumour evolution

Author

Watkins, Thomas BK, Lim, Emilia L, Petkovic, Marina, Elizalde, Sergi, Birkbak, Nicolai J, Wilson, Gareth A, Moore, David A, Grönroos, Eva, Rowan, Andrew, Dewhurst, Sally M, Demeulemeester, Jonas, Dentro, Stefan C, Horswell, Stuart, Au, Lewis, Haase, Kerstin, Escudero, Mickael, Rosenthal, Rachel, Bakir, Maise Al, Xu, Hang, Litchfield, Kevin, Lu, Wei Ting, Mourikis, Thanos P, Dietzen, Michelle, Spain, Lavinia, Cresswell, George D, Biswas, Dhruva, Lamy, Philippe, Nordentoft, Iver, Harbst, Katja, Castro-Giner, Francesc, Yates, Lucy R, Caramia, Franco, Jaulin, Fanny, Vicier, Cécile, Tomlinson, Ian PM, Brastianos, Priscilla K, Cho, Raymond J, Bastian, Boris C, Dyrskjøt, Lars, Jönsson, Göran B, Savas, Peter, Loi, Sherene, Campbell, Peter J, Andre, Fabrice, Luscombe, Nicholas M, Steeghs, Neeltje, Tjan-Heijnen, Vivianne CG, Szallasi, Zoltan, Turajlic, Samra, Jamal-Hanjani, Mariam, Van Loo, Peter, Bakhoum, Samuel F, Schwarz, Roland F, McGranahan, Nicholas, and Swanton, Charles

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Cancer, Human Genome, Chromosomal Instability, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 8, Clone Cells, Cyclin E, DNA Copy Number Variations, Evolution, Molecular, Female, Humans, Karyotype, Loss of Heterozygosity, Male, Mutagenesis, Neoplasm Metastasis, Neoplasms, Oncogene Proteins, General Science & Technology
Abstract

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.

Published
2020

12. Classification of intraoperative adverse events in visceral surgery

Author

ten Broek, R.B., Rosman, C., Aduse-Poku, M., Aghlamandi, S., Bissett, I., Blanc, C., Brandt, C., Bruppacher, H.R., Bucher, H.C., Clancy, C., Clavien, P.-A., Delrio, P., Espin, E., Engel, A., Gomes, N.V., Galanos-Demiris, K., Gecim, E., Ghaffari, S., Gié, O., Goebel, B., Hahnloser, D., Herbst, F., Ionnadis, O., Joller, S., Kang, Soojin, Kirchhoff, P., Loveday, B., Martín, R., Mayr, J., Meier, S., Murugesan, J., Nally, D., O’Grady, G., Ozcelik, M., Pace, U., Passeri, M., Rabanser, S., Ranter, B., Rega, D., Ridgway, P.F., Schmid, R., Schumacher, P., Solis, A., Steiner, L.A., Villarino, L., Vrochides, D., Gawria, Larsa, Rosenthal, Rachel, van Goor, Harry, and Dell-Kuster, Salome

Published
2022
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13. Immune editing and surveillance in cancer evolution

Author

Rosenthal, Rachel Suzanne

Subjects
616.99
Abstract

Cancer is an evolutionary disease, reliant on genetic diversity and sculpted by selective forces from the immune microenvironment. Here, I use genomics data to decipher the tumor’s evolutionary trajectory and corresponding shifts in the immune contexture to elucidate the events governing tumor immunogenicity and the immune evasive mechanisms evolved by the tumor. To better understand the mutational processes contributing to intratumor heterogeneity in individual tumors, a method to quantify the activity of mutational processes in a single tumor sample was developed and applied to temporally dissected mutations. The clinical relevance of intratumor heterogeneity was examined in the context of immune recognition and modulation. Increased clonal neoantigen burden and minimal neoantigen intratumor heterogeneity were found to associate with improved patient outcome, both in the treatment-naïve and immunotherapy-treated setting. The identification of T-cells recognizing clonal neoantigens further supported the clinical importance of targeting neoantigens present in every cancer cell. Mechanisms of immune evasion were considered through the development of a method to identify loss-of-heterozygosity at the HLA locus, overcoming the challenges posed by the polymorphic nature of the locus. HLA loss-of-heterozygosity was found to be a frequent subclonal event in NSCLC, under strong selective pressure and associated with increased subclonal neoantigen burden. Finally, the immune microenvironment was examined through multi-region RNAseq, permitting the quantification of immune infiltration and allowing for the identification of heterogeneously immune infiltrated tumors. Supporting the interplay between genetic events and the immune contexture, a relationship between the genomic features of the tumor and immune infiltration was observed, with HLA loss-of-heterozygosity specifically identified as occurring within a highly active immune microenvironment. This thesis shows how an improved understanding of the relationship between the tumor and the immune system can illuminate features dictating immune recognition and evasion and how that knowledge may inform the development and implementation of successful immunotherapy.

Published
2018

14. Using DNA sequencing data to quantify T cell fraction and therapy response

Author

Bentham, Robert, Litchfield, Kevin, Watkins, Thomas B. K., Lim, Emilia L., Rosenthal, Rachel, Martínez-Ruiz, Carlos, Hiley, Crispin T., Bakir, Maise Al, Salgado, Roberto, Moore, David A., Jamal-Hanjani, Mariam, Birkbak, Nicolai J., Escudero, Mickael, Stewart, Aengus, Rowan, Andrew, and Goldman, Jacki

Subjects
Nucleotide sequencing -- Methods, T cells -- Physiological aspects -- Genetic aspects, Cellular therapy -- Methods, DNA sequencing -- Methods, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy.sup.1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-[alpha] gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes. A robust, cost-effective technique based on whole-exome sequencing data can be used to characterize immune infiltrates, relate the extent of these infiltrates to somatic changes in tumours, and enables prediction of tumour responses to immune checkpoint inhibition therapy., Author(s): Robert Bentham [sup.1] [sup.2] , Kevin Litchfield [sup.2] [sup.3] , Thomas B. K. Watkins [sup.4] , Emilia L. Lim [sup.2] [sup.4] , Rachel Rosenthal [sup.4] , Carlos Martínez-Ruiz [sup.1] [...]

Published
2021
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15. Prospective validation of classification of intraoperative adverse events (ClassIntra) : international, multicentre cohort study

Author

Dell-Kuster, Salome, Gomes, Nuno V, Gawria, Larsa, Aghlmandi, Soheila, Aduse-Poku, Maame, Bissett, Ian, Blanc, Catherine, Brandt, Christian, ten Broek, Richard B, Bruppacher, Heinz R, Clancy, Cillian, Delrio, Paolo, Espin, Eloy, Galanos-Demiris, Konstantinos, Gecim, Ethem, Ghaffari, Shahbaz, Gié, Olivier, Goebel, Barbara, Hahnloser, Dieter, Herbst, Friedrich, Orestis, Ioannidis, Joller, Sonja, Kang, Soojin, Martín, Rocio, Mayr, Johannes, Meier, Sonja, Murugesan, Jothi, Nally, Deirdre, Ozcelik, Menekse, Pace, Ugo, Passeri, Michael, Rabanser, Simone, Ranter, Barbara, Rega, Daniela, Ridgway, Paul F, Rosman, Camiel, Schmid, Roger, Schumacher, Philippe, Solis-Pena, Alejandro, Villarino, Laura, Vrochides, Dionisios, Engel, Alexander, O’Grady, Greg, Loveday, Benjamin, Steiner, Luzius A, Van Goor, Harry, Bucher, Heiner C, Clavien, Pierre-Alain, Kirchhoff, Philipp, and Rosenthal, Rachel

Published
2020

18. Geospatial immune variability illuminates differential evolution of lung adenocarcinoma

Author

AbdulJabbar, Khalid, Raza, Shan E. Ahmed, Rosenthal, Rachel, Jamal-Hanjani, Mariam, Veeriah, Selvaraju, Akarca, Ayse, and Lund, Tom

Subjects
Immune system -- Genetic aspects -- Health aspects, Lung cancer, Non-small cell -- Development and progression -- Genetic aspects, Biological sciences, Health
Abstract

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape.sup.1-5. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort.sup.6. Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer-stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes. Multiregion spatial histology, exome and transcriptome data from patients with non-small cell lung cancer suggest that cancer subclones from immune cold regions diversify later than subclones from immune hot regions, Author(s): Khalid AbdulJabbar [sup.1] [sup.2] , Shan E. Ahmed Raza [sup.1] [sup.2] , Rachel Rosenthal [sup.3] [sup.4] , Mariam Jamal-Hanjani [sup.3] [sup.5] , Selvaraju Veeriah [sup.3] [sup.4] , Ayse Akarca [...]

Published
2020
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19. A clonal expression biomarker associates with lung cancer mortality

Author

Biswas, Dhruva, Birkbak, Nicolai J., Rosenthal, Rachel, Hiley, Crispin T., Lim, Emilia L., Papp, Krisztian, and Boeing, Stefan

Subjects
RNA sequencing -- Usage, Lung cancer -- Genetic aspects -- Care and treatment, Genetic transcription -- Research, Biological markers -- Research, Biological sciences, Health
Abstract

An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage.sup.1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types.sup.2-6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types. TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers., Author(s): Dhruva Biswas [sup.1] [sup.2] [sup.3] , Nicolai J. Birkbak [sup.1] [sup.3] [sup.4] [sup.5] , Rachel Rosenthal [sup.1] [sup.2] [sup.3] , Crispin T. Hiley [sup.1] [sup.3] , Emilia L. Lim [...]

Published
2019
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20. The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Author

Ghorani, Ehsan, Reading, James L., Henry, Jake Y., Massy, Marc Robert de, Rosenthal, Rachel, Turati, Virginia, Joshi, Kroopa, Furness, Andrew J. S., Ben Aissa, Assma, Saini, Sunil Kumar, Ramskov, Sofie, Georgiou, Andrew, Sunderland, Mariana Werner, Wong, Yien Ning Sophia, Mucha, Maria Vila De, Day, William, Galvez-Cancino, Felipe, Becker, Pablo D., Uddin, Imran, Oakes, Theres, Ismail, Mazlina, Ronel, Tahel, Woolston, Annemarie, Jamal-Hanjani, Mariam, Veeriah, Selvaraju, Birkbak, Nicolai J., Wilson, Gareth A., Litchfield, Kevin, Conde, Lucia, Guerra-Assunção, José Afonso, Blighe, Kevin, Biswas, Dhruva, Salgado, Roberto, Lund, Tom, Bakir, Maise Al, Moore, David A., Hiley, Crispin T., Loi, Sherene, Sun, Yuxin, Yuan, Yinyin, AbdulJabbar, Khalid, Turajilic, Samra, Herrero, Javier, Enver, Tariq, Hadrup, Sine R., Hackshaw, Allan, Peggs, Karl S., McGranahan, Nicholas, Chain, Benny, Swanton, Charles, and Quezada, Sergio A.

Published
2020
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21. Neoantigen-directed immune escape in lung cancer evolution

Author

Rosenthal, Rachel, Cadieux, Elizabeth Larose, Salgado, Roberto, Bakir, Maise Al, Moore, David A., Hiley, Crispin T., Lund, Tom, Tanić, Miljana, Reading, James L., Joshi, Kroopa, Henry, Jake Y., Ghorani, Ehsan, Wilson, Gareth A., Birkbak, Nicolai J., Jamal-Hanjani, Mariam, Veeriah, Selvaraju, Szallasi, Zoltan, Loi, Sherene, Hellmann, Matthew D., Feber, Andrew, Chain, Benny, Herrero, Javier, Quezada, Sergio A., Demeulemeester, Jonas, Van Loo, Peter, Beck, Stephan, McGranahan, Nicholas, Swanton, Charles, and The TRACERx consortium

Published
2019
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24. Table S2 from Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer

Author

Pennycuick, Adam, primary, Teixeira, Vitor H., primary, AbdulJabbar, Khalid, primary, Raza, Shan E. Ahmed, primary, Lund, Tom, primary, Akarca, Ayse U., primary, Rosenthal, Rachel, primary, Kalinke, Lukas, primary, Chandrasekharan, Deepak P., primary, Pipinikas, Christodoulos P., primary, Lee-Six, Henry, primary, Hynds, Robert E., primary, Gowers, Kate H.C., primary, Henry, Jake Y., primary, Millar, Fraser R., primary, Hagos, Yeman B., primary, Denais, Celine, primary, Falzon, Mary, primary, Moore, David A., primary, Antoniou, Sophia, primary, Durrenberger, Pascal F., primary, Furness, Andrew J., primary, Carroll, Bernadette, primary, Marceaux, Claire, primary, Asselin-Labat, Marie-Liesse, primary, Larson, William, primary, Betts, Courtney, primary, Coussens, Lisa M., primary, Thakrar, Ricky M., primary, George, Jeremy, primary, Swanton, Charles, primary, Thirlwell, Christina, primary, Campbell, Peter J., primary, Marafioti, Teresa, primary, Yuan, Yinyin, primary, Quezada, Sergio A., primary, McGranahan, Nicholas, primary, and Janes, Sam M., primary

Published
2023
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25. Data from Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer

Author

Pennycuick, Adam, primary, Teixeira, Vitor H., primary, AbdulJabbar, Khalid, primary, Raza, Shan E. Ahmed, primary, Lund, Tom, primary, Akarca, Ayse U., primary, Rosenthal, Rachel, primary, Kalinke, Lukas, primary, Chandrasekharan, Deepak P., primary, Pipinikas, Christodoulos P., primary, Lee-Six, Henry, primary, Hynds, Robert E., primary, Gowers, Kate H.C., primary, Henry, Jake Y., primary, Millar, Fraser R., primary, Hagos, Yeman B., primary, Denais, Celine, primary, Falzon, Mary, primary, Moore, David A., primary, Antoniou, Sophia, primary, Durrenberger, Pascal F., primary, Furness, Andrew J., primary, Carroll, Bernadette, primary, Marceaux, Claire, primary, Asselin-Labat, Marie-Liesse, primary, Larson, William, primary, Betts, Courtney, primary, Coussens, Lisa M., primary, Thakrar, Ricky M., primary, George, Jeremy, primary, Swanton, Charles, primary, Thirlwell, Christina, primary, Campbell, Peter J., primary, Marafioti, Teresa, primary, Yuan, Yinyin, primary, Quezada, Sergio A., primary, McGranahan, Nicholas, primary, and Janes, Sam M., primary

Published
2023
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26. Supplementary Data from Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer

Author

Pennycuick, Adam, primary, Teixeira, Vitor H., primary, AbdulJabbar, Khalid, primary, Raza, Shan E. Ahmed, primary, Lund, Tom, primary, Akarca, Ayse U., primary, Rosenthal, Rachel, primary, Kalinke, Lukas, primary, Chandrasekharan, Deepak P., primary, Pipinikas, Christodoulos P., primary, Lee-Six, Henry, primary, Hynds, Robert E., primary, Gowers, Kate H.C., primary, Henry, Jake Y., primary, Millar, Fraser R., primary, Hagos, Yeman B., primary, Denais, Celine, primary, Falzon, Mary, primary, Moore, David A., primary, Antoniou, Sophia, primary, Durrenberger, Pascal F., primary, Furness, Andrew J., primary, Carroll, Bernadette, primary, Marceaux, Claire, primary, Asselin-Labat, Marie-Liesse, primary, Larson, William, primary, Betts, Courtney, primary, Coussens, Lisa M., primary, Thakrar, Ricky M., primary, George, Jeremy, primary, Swanton, Charles, primary, Thirlwell, Christina, primary, Campbell, Peter J., primary, Marafioti, Teresa, primary, Yuan, Yinyin, primary, Quezada, Sergio A., primary, McGranahan, Nicholas, primary, and Janes, Sam M., primary

Published
2023
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27. Timing of surgical antimicrobial prophylaxis: a phase 3 randomised controlled trial

Author

Weber, Walter P, Mujagic, Edin, Zwahlen, Marcel, Bundi, Marcel, Hoffmann, Henry, Soysal, Savas D, Kraljević, Marko, Delko, Tarik, von Strauss, Marco, Iselin, Lukas, Da Silva, Richard X Sousa, Zeindler, Jasmin, Rosenthal, Rachel, Misteli, Heidi, Kindler, Christoph, Müller, Peter, Saccilotto, Ramon, Lugli, Andrea Kopp, Kaufmann, Mark, Gürke, Lorenz, von Holzen, Urs, Oertli, Daniel, Bucheli-Laffer, Evelin, Landin, Julia, Widmer, Andreas F, Fux, Christoph A, and Marti, Walter R

Published
2017
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28. Premature Discontinuation of Pediatric Randomized Controlled Trials: A Retrospective Cohort Study

Author

Schandelmaier, Stefan, Tomonaga, Yuki, Bassler, Dirk, Meerpohl, Joerg J., von Elm, Erik, You, John J., Bluemle, Anette, Lamontagne, Francois, Saccilotto, Ramon, Amstutz, Alain, Bengough, Theresa, Stegert, Mihaela, Olu, Kelechi K., Tikkinen, Kari A.O., Neumann, Ignacio, Carrasco-Labra, Alonso, Faulhaber, Markus, Mulla, Sohail M., Mertz, Dominik, Akl, Elie A., Sun, Xin, Busse, Jason W., Ferreira-González, Ignacio, Nordmann, Alain, Gloy, Viktoria, Raatz, Heike, Moja, Lorenzo, Rosenthal, Rachel, Ebrahim, Shanil, Vandvik, Per O., Johnston, Bradley C., Walter, Martin A., Burnand, Bernard, Schwenkglenks, Matthias, Hemkens, Lars G., Guyatt, Gordon, Bucher, Heiner C., Kasenda, Benjamin, and Briel, Matthias

Published
2017
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30. ZONE

Author

Rosenthal, Rachel

Published
2001

32. Body composition and lung cancer-associated cachexia in TRACERx

Author

Al-Sawaf, Othman, Weiss, Jakob, Skrzypski, Marcin, Lam, Jie Min, Karasaki, Takahiro, Zambrana, Francisco, Kidd, Andrew C, Frankell, Alexander M, Watkins, Thomas BK, Martinez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Huebner, Ariana, Al Bakir, Maise, Sokac, Mateo, Collins, Susie, Veeriah, Selvaraju, Magno, Neil, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Ward, Sophia, Jayanth, Nick, Salgado, Roberto, Bridge, Christopher P, Christiani, David C, Mak, Raymond H, Bay, Camden, Rosenthal, Michael, Sattar, Naveed, Welsh, Paul, Liu, Ying, Perrimon, Norbert, Popuri, Karteek, Beg, Mirza Faisal, McGranahan, Nicholas, Hackshaw, Allan, Breen, Danna M, O'Rahilly, Stephen, Birkbak, Nicolai J, Aerts, Hugo JWL, Jamal-Hanjani, Mariam, Swanton, Charles, Lester, Jason F, 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, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, 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, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Van Loo, Peter, Szallasi, Zoltan, Kisistok, Judit, Diossy, Miklos, Demeulemeester, Jonas, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Abbosh, Christopher, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Hiley, Crispin T, Moore, David A, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Cadieux, Elizabeth Larose, Lim, Emilia L, Colliver, Emma, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Hartley, John A, Peggs, Karl S, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Grigoriadis, Kristiana, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Hill, Mark S, Dietzen, Michelle, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Pich, Oriol, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Zaccaria, Simone, Hessey, Sonya, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, 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, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, 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, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Male, Proteomics, Cachexia, Lung Neoplasms, Antigens, Neoplasm, Carcinoma, Non-Small-Cell Lung, Body Weight, Body Composition, Humans, Neoplasm Recurrence, Local, Muscle, Skeletal, Neoplasm Proteins
Abstract

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

33. The evolution of non-small cell lung cancer metastases in TRACERx

Author

Al Bakir, Maise, Huebner, Ariana, Martinez-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, 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, Peggs, Karl S, Van Loo, Peter, Dive, Caroline, Hackshaw, Allan, Birkbak, Nicolai J, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Lester, Jason F, 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, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Benafif, Sarah, 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, Krebs, Matthew G, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Puttick, Clare, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Black, James RM, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, 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, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Bentham, Robert, 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, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, 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, Lim, Eric, 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, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Clonal Evolution, Cohort Studies, Evolution, Molecular, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Disease Progression, Humans, Neoplasm Metastasis, Neoplasm Recurrence, Local, Clone Cells
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. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

34. 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

35. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Author

Karasaki, Takahiro, Moore, David A, Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Magno, Neil, Ward, Sophia, Al Bakir, Maise, Watkins, Thomas BK, Grigoriadis, Kristiana, Huebner, Ariana, Hill, Mark S, Frankell, Alexander M, Abbosh, Christopher, Puttick, Clare, Zhai, Haoran, Gimeno-Valiente, Francisco, Saghafinia, Sadegh, Kanu, Nnennaya, Dietzen, Michelle, Pich, Oriol, Lim, Emilia L, Martinez-Ruiz, Carlos, Black, James RM, Biswas, Dhruva, Campbell, Brittany B, Lee, Claudia, Colliver, Emma, Enfield, Katey SS, Hessey, Sonya, Hiley, Crispin T, Zaccaria, Simone, Litchfield, Kevin, Birkbak, Nicolai J, Cadieux, Elizabeth Larose, Demeulemeester, Jonas, Van Loo, Peter, Adusumilli, Prasad R, Tan, Kay See, Cheema, Waseem, Sanchez-Vega, Francisco, Jones, David R, Rekhtman, Natasha, Travis, William D, Hackshaw, Allan, Marafioti, Teresa, Salgado, Roberto, Le Quesne, John, Nicholson, Andrew G, McGranahan, Nicholas, Swanton, Charles, Jamal-Hanjani, Mariam, Lester, Jason F, 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, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, 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, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Castignani, Carla, Bailey, Chris, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Peggs, Karl S, Selvaraju, Kayalvizhi, Thol, Kerstin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Prymas, Paulina, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, 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, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, 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, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
TRACERx Consortium
Abstract

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

36. Supplementary methods from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

Author

Conforti, Fabio, primary, Pala, Laura, primary, Pagan, Eleonora, primary, Bagnardi, Vincenzo, primary, De Pas, Tommaso, primary, Queirolo, Paola, primary, Pennacchioli, Elisabetta, primary, Catania, Chiara, primary, Cocorocchio, Emilia, primary, Ferrucci, Pier Francesco, primary, Saponara, Maristella, primary, Orsolini, Gianmarco, primary, Zagami, Paola, primary, Nicoló, Eleonora, primary, De Marinis, Filippo, primary, Tortora, Giampaolo, primary, Bria, Emilio, primary, Minucci, Saverio, primary, Joffe, Hadine, primary, Veronesi, Paolo, primary, Wargo, Jennifer, primary, Rosenthal, Rachel, primary, Swanton, Charles, primary, Mantovani, Alberto, primary, Gelber, Richard D., primary, Viale, Giuseppe, primary, Goldhirsch, Aron, primary, and Giaccone, Giuseppe, primary

Published
2023
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37. Table S2 from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

Author

Conforti, Fabio, primary, Pala, Laura, primary, Pagan, Eleonora, primary, Bagnardi, Vincenzo, primary, De Pas, Tommaso, primary, Queirolo, Paola, primary, Pennacchioli, Elisabetta, primary, Catania, Chiara, primary, Cocorocchio, Emilia, primary, Ferrucci, Pier Francesco, primary, Saponara, Maristella, primary, Orsolini, Gianmarco, primary, Zagami, Paola, primary, Nicoló, Eleonora, primary, De Marinis, Filippo, primary, Tortora, Giampaolo, primary, Bria, Emilio, primary, Minucci, Saverio, primary, Joffe, Hadine, primary, Veronesi, Paolo, primary, Wargo, Jennifer, primary, Rosenthal, Rachel, primary, Swanton, Charles, primary, Mantovani, Alberto, primary, Gelber, Richard D., primary, Viale, Giuseppe, primary, Goldhirsch, Aron, primary, and Giaccone, Giuseppe, primary

Published
2023
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38. Figure S1 from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

Author

Conforti, Fabio, primary, Pala, Laura, primary, Pagan, Eleonora, primary, Bagnardi, Vincenzo, primary, De Pas, Tommaso, primary, Queirolo, Paola, primary, Pennacchioli, Elisabetta, primary, Catania, Chiara, primary, Cocorocchio, Emilia, primary, Ferrucci, Pier Francesco, primary, Saponara, Maristella, primary, Orsolini, Gianmarco, primary, Zagami, Paola, primary, Nicoló, Eleonora, primary, De Marinis, Filippo, primary, Tortora, Giampaolo, primary, Bria, Emilio, primary, Minucci, Saverio, primary, Joffe, Hadine, primary, Veronesi, Paolo, primary, Wargo, Jennifer, primary, Rosenthal, Rachel, primary, Swanton, Charles, primary, Mantovani, Alberto, primary, Gelber, Richard D., primary, Viale, Giuseppe, primary, Goldhirsch, Aron, primary, and Giaccone, Giuseppe, primary

Published
2023
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39. Legends of supplementary figure 1 and 2 from Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

Author

Conforti, Fabio, primary, Pala, Laura, primary, Pagan, Eleonora, primary, Bagnardi, Vincenzo, primary, De Pas, Tommaso, primary, Queirolo, Paola, primary, Pennacchioli, Elisabetta, primary, Catania, Chiara, primary, Cocorocchio, Emilia, primary, Ferrucci, Pier Francesco, primary, Saponara, Maristella, primary, Orsolini, Gianmarco, primary, Zagami, Paola, primary, Nicoló, Eleonora, primary, De Marinis, Filippo, primary, Tortora, Giampaolo, primary, Bria, Emilio, primary, Minucci, Saverio, primary, Joffe, Hadine, primary, Veronesi, Paolo, primary, Wargo, Jennifer, primary, Rosenthal, Rachel, primary, Swanton, Charles, primary, Mantovani, Alberto, primary, Gelber, Richard D., primary, Viale, Giuseppe, primary, Goldhirsch, Aron, primary, and Giaccone, Giuseppe, primary

Published
2023
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41. An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules

Author

Stegert, Mihaela, Kasenda, Benjamin, Elm, Erik von, You, John J., Blümle, Anette, Tomonaga, Yuki, Saccilotto, Ramon, Amstutz, Alain, Bengough, Theresa, Meerpohl, Joerg J., Tikkinen, Kari A.O., Neumann, Ignacio, Carrasco-Labra, Alonso, Faulhaber, Markus, Mulla, Sohail, Mertz, Dominik, Akl, Elie A., Bassler, Dirk, Busse, Jason W., Ferreira-González, Ignacio, Lamontagne, Francois, Nordmann, Alain, Gloy, Viktoria, Olu, Kelechi Kalu, Raatz, Heike, Moja, Lorenzo, Rosenthal, Rachel, Ebrahim, Shanil, Schandelmaier, Stefan, Sun, Xin, Vandvik, Per O., Johnston, Bradley C., Walter, Martin A., Burnand, Bernard, Schwenkglenks, Matthias, Hemkens, Lars G., Bucher, Heiner C., Guyatt, Gordon H., Briel, Matthias, and von Elm, Erik

Published
2016
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42. 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

43. Augmented Reality Assisted Laparoscopic Partial Nephrectomy

Author

Schneider, Adrian, Pezold, Simon, Sauer, Andreas, Ebbing, Jan, Wyler, Stephen, Rosenthal, Rachel, Cattin, Philippe C., Hutchison, David, Series editor, Kanade, Takeo, Series editor, Kittler, Josef, Series editor, Kleinberg, Jon M., Series editor, Kobsa, Alfred, Series editor, Mattern, Friedemann, Series editor, Mitchell, John C., Series editor, Naor, Moni, Series editor, Nierstrasz, Oscar, Series editor, Pandu Rangan, C., Series editor, Steffen, Bernhard, Series editor, Terzopoulos, Demetri, Series editor, Tygar, Doug, Series editor, Weikum, Gerhard, Series editor, Golland, Polina, editor, Hata, Nobuhiko, editor, Barillot, Christian, editor, Hornegger, Joachim, editor, and Howe, Robert, editor

Published
2014
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46. 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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