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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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5. Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Author

Ng, Kevin W., Boumelha, Jesse, Enfield, Katey S. S., 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 T. C., Martínez-Ruiz, Carlos, Puttick, Clare, Black, James R. M., Watkins, Thomas B. K., 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, Hiley, Crispin T., Litchfield, Kevin, McGranahan, Nicholas, Jamal-Hanjani, Mariam, Larkin, James, Lee, Se-Hoon, Turajlic, Samra, Swanton, Charles, Downward, Julian, and Kassiotis, George

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

Author

Al Bakir, Maise, Huebner, Ariana, Martínez-Ruiz, Carlos, Grigoriadis, Kristiana, Watkins, Thomas B. K., 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, Jamal-Hanjani, Mariam, McGranahan, Nicholas, and Swanton, Charles

Published
2023
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7. 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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8. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Author

Abbosh, Christopher, Frankell, Alexander M., Harrison, Thomas, Kisistok, Judit, Garnett, Aaron, Johnson, Laura, Veeriah, Selvaraju, Moreau, Mike, Chesh, Adrian, Chaunzwa, Tafadzwa L., Weiss, Jakob, Schroeder, Morgan R., Ward, Sophia, Grigoriadis, Kristiana, Shahpurwalla, Aamir, Litchfield, Kevin, Puttick, Clare, Biswas, Dhruva, Karasaki, Takahiro, Black, James R. M., Martínez-Ruiz, Carlos, Bakir, Maise Al, Pich, Oriol, Watkins, Thomas B. K., Lim, Emilia L., Huebner, Ariana, Moore, David A., Godin-Heymann, Nadia, L’Hernault, Anne, Bye, Hannah, Odell, Aaron, Roberts, Paula, Gomes, Fabio, Patel, Akshay J., Manzano, Elizabeth, Hiley, Crispin T., Carey, Nicolas, Riley, Joan, Cook, Daniel E., Hodgson, Darren, Stetson, Daniel, Barrett, J. Carl, Kortlever, Roderik M., Evan, Gerard I., Hackshaw, Allan, Daber, Robert D., Shaw, Jacqui A., Aerts, Hugo J. W. L., Licon, Abel, Stahl, Josh, Jamal-Hanjani, Mariam, Birkbak, Nicolai J., McGranahan, Nicholas, and Swanton, Charles

Published
2023
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9. 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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10. 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, Bakir, Maise Al, Watkins, Thomas B. K., 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., Martínez-Ruiz, Carlos, Black, James R. M., Biswas, Dhruva, Campbell, Brittany B., Lee, Claudia, Colliver, Emma, Enfield, Katey S. S., Hessey, Sonya, Hiley, Crispin T., Zaccaria, Simone, Litchfield, Kevin, Birkbak, Nicolai J., Cadieux, Elizabeth Larose, Demeulemeester, Jonas, Van Loo, Peter, Adusumilli, Prasad S., 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, and Jamal-Hanjani, Mariam

Published
2023
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11. 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 B. K., Martínez-Ruiz, Carlos, Puttick, Clare, Black, James R. M., Huebner, Ariana, Bakir, Maise Al, Sokač, 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 J. W. L., Jamal-Hanjani, Mariam, and Swanton, Charles

Published
2023
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12. 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

13. Exploring the molecular landscape of cancer of unknown primary: A comparative analysis with other metastatic cancers.

Author

Andersen, Laura, Christensen, Ditte S., Kjær, Asbjørn, Knudsen, Michael, Andersen, Andreas K., Laursen, Maria B., Ahrenfeldt, Johanne, Laursen, Britt E., and Birkbak, Nicolai J.

Abstract

Cancer of unknown primary (CUP) tumors are biologically very heterogeneous, which complicates stratification of patients for treatment. Consequently, these patients face limited treatment options and a poor prognosis. With this study, we aim to expand on the current knowledge of CUP biology by analyzing two cohorts: a well‐characterized cohort of 44 CUP patients, and 213 metastatic patients with known primary. These cohorts were treated at the same institution and characterized by identical molecular assessments. Through comparative analysis of genomic and transcriptomic data, we found that CUP tumors were characterized by high expression of immune‐related genes and pathways compared to other metastatic tumors. Moreover, CUP tumors uniformly demonstrated high levels of tumor‐infiltrating leukocytes and circulating T cells, indicating a strong immune response. Finally, the genetic landscape of CUP tumors resembled that of other metastatic cancers and demonstrated mutations in established cancer genes. In conclusion, CUP tumors possess a distinct immunophenotype that distinguishes them from other metastatic cancers. These results may suggest an immune response in CUP that facilitates metastatic tumor growth while limiting growth of the primary tumor. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Chromosomal instability drives metastasis through a cytosolic DNA response

Author

Bakhoum, Samuel F, Ngo, Bryan, Laughney, Ashley M, Cavallo, Julie-Ann, Murphy, Charles J, Ly, Peter, Shah, Pragya, Sriram, Roshan K, Watkins, Thomas BK, Taunk, Neil K, Duran, Mercedes, Pauli, Chantal, Shaw, Christine, Chadalavada, Kalyani, Rajasekhar, Vinagolu K, Genovese, Giulio, Venkatesan, Subramanian, Birkbak, Nicolai J, McGranahan, Nicholas, Lundquist, Mark, LaPlant, Quincey, Healey, John H, Elemento, Olivier, Chung, Christine H, Lee, Nancy Y, Imielenski, Marcin, Nanjangud, Gouri, Pe’er, Dana, Cleveland, Don W, Powell, Simon N, Lammerding, Jan, Swanton, Charles, and Cantley, Lewis C

Subjects
Genetics, HIV/AIDS, Aetiology, 2.1 Biological and endogenous factors, Cancer, Animals, Brain Neoplasms, Breast Neoplasms, Carcinoma, Squamous Cell, Cell Line, Chromosomal Instability, Chromosome Segregation, Cytosol, DNA, Neoplasm, Female, Head and Neck Neoplasms, Humans, Inflammation, Membrane Proteins, Mesoderm, Mice, Micronuclei, Chromosome-Defective, NF-kappa B, Neoplasm Metastasis, Nucleotidyltransferases, Xenograft Model Antitumor Assays, General Science & Technology
Abstract

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Published
2018

15. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers

Author

Blakely, Collin M, Watkins, Thomas BK, Wu, Wei, Gini, Beatrice, Chabon, Jacob J, McCoach, Caroline E, McGranahan, Nicholas, Wilson, Gareth A, Birkbak, Nicolai J, Olivas, Victor R, Rotow, Julia, Maynard, Ashley, Wang, Victoria, Gubens, Matthew A, Banks, Kimberly C, Lanman, Richard B, Caulin, Aleah F, St John, John, Cordero, Anibal R, Giannikopoulos, Petros, Simmons, Andrew D, Mack, Philip C, Gandara, David R, Husain, Hatim, Doebele, Robert C, Riess, Jonathan W, Diehn, Maximilian, Swanton, Charles, and Bivona, Trever G

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Cancer, Rare Diseases, Lung, Clinical Research, Lung Cancer, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Class I Phosphatidylinositol 3-Kinases, Clonal Evolution, Cyclin-Dependent Kinases, ErbB Receptors, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Lung Neoplasms, Mutation, Neoplasm Staging, Protein Kinase Inhibitors, Wnt Signaling Pathway, beta Catenin, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.

Published
2017

16. 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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17. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

Author

Lindskrog, Sia Viborg, Prip, Frederik, Lamy, Philippe, Taber, Ann, Groeneveld, Clarice S., Birkenkamp-Demtröder, Karin, Jensen, Jørgen Bjerggaard, Strandgaard, Trine, Nordentoft, Iver, Christensen, Emil, Sokac, Mateo, Birkbak, Nicolai J., Maretty, Lasse, Hermann, Gregers G., Petersen, Astrid C., Weyerer, Veronika, Grimm, Marc-Oliver, Horstmann, Marcus, Sjödahl, Gottfrid, Höglund, Mattias, Steiniche, Torben, Mogensen, Karin, de Reyniès, Aurélien, Nawroth, Roman, Jordan, Brian, Lin, Xiaoqi, Dragicevic, Dejan, Ward, Douglas G., Goel, Anshita, Hurst, Carolyn D., Raman, Jay D., Warrick, Joshua I., Segersten, Ulrika, Sikic, Danijel, van Kessel, Kim E. M., Maurer, Tobias, Meeks, Joshua J., DeGraff, David J., Bryan, Richard T., Knowles, Margaret A., Simic, Tatjana, Hartmann, Arndt, Zwarthoff, Ellen C., Malmström, Per-Uno, Malats, Núria, Real, Francisco X., and Dyrskjøt, Lars

Published
2021
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18. 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. Foundation Models for Quantitative Biomarker Discovery in Cancer Imaging

Author

Pai, Suraj, primary, Bontempi, Dennis, additional, Hadzic, Ibrahim, additional, Prudente, Vasco, additional, Sokač, Mateo, additional, Chaunzwa, Tafadzwa L., additional, Bernatz, Simon, additional, Hosny, Ahmed, additional, Mak, Raymond H, additional, Birkbak, Nicolai J, additional, and Aerts, Hugo JWL, additional

Published
2023
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22. 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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23. 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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29. Data from Tracking the Genomic Evolution of Esophageal Adenocarcinoma through Neoadjuvant Chemotherapy

Author

Murugaesu, Nirupa, primary, Wilson, Gareth A., primary, Birkbak, Nicolai J., primary, Watkins, Thomas B.K., primary, McGranahan, Nicholas, primary, Kumar, Sacheen, primary, Abbassi-Ghadi, Nima, primary, Salm, Max, primary, Mitter, Richard, primary, Horswell, Stuart, primary, Rowan, Andrew, primary, Phillimore, Benjamin, primary, Biggs, Jennifer, primary, Begum, Sharmin, primary, Matthews, Nik, primary, Hochhauser, Daniel, primary, Hanna, George B., primary, and Swanton, Charles, primary

Published
2023
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30. Supplementary Data from MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy

Author

Neupane, Manish, primary, Clark, Allison P., primary, Landini, Serena, primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Lim, Elgene, primary, Culhane, Aedin C., primary, Barry, William T., primary, Schumacher, Steven E., primary, Beroukhim, Rameen, primary, Szallasi, Zoltan, primary, Vidal, Marc, primary, Hill, David E., primary, and Silver, Daniel P., primary

Published
2023
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31. Supplementary Figures S1 - S6 from MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy

Author

Neupane, Manish, primary, Clark, Allison P., primary, Landini, Serena, primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Lim, Elgene, primary, Culhane, Aedin C., primary, Barry, William T., primary, Schumacher, Steven E., primary, Beroukhim, Rameen, primary, Szallasi, Zoltan, primary, Vidal, Marc, primary, Hill, David E., primary, and Silver, Daniel P., primary

Published
2023
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32. Data from Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents

Author

Birkbak, Nicolai J., primary, Wang, Zhigang C., primary, Kim, Ji-Young, primary, Eklund, Aron C., primary, Li, Qiyuan, primary, Tian, Ruiyang, primary, Bowman-Colin, Christian, primary, Li, Yang, primary, Greene-Colozzi, April, primary, Iglehart, J. Dirk, primary, Tung, Nadine, primary, Ryan, Paula D., primary, Garber, Judy E., primary, Silver, Daniel P., primary, Szallasi, Zoltan, primary, and Richardson, Andrea L., primary

Published
2023
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33. Supplementary Methods from MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy

Author

Neupane, Manish, primary, Clark, Allison P., primary, Landini, Serena, primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Lim, Elgene, primary, Culhane, Aedin C., primary, Barry, William T., primary, Schumacher, Steven E., primary, Beroukhim, Rameen, primary, Szallasi, Zoltan, primary, Vidal, Marc, primary, Hill, David E., primary, and Silver, Daniel P., primary

Published
2023
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34. Supplementary Table S3 from Tracking the Genomic Evolution of Esophageal Adenocarcinoma through Neoadjuvant Chemotherapy

Author

Murugaesu, Nirupa, primary, Wilson, Gareth A., primary, Birkbak, Nicolai J., primary, Watkins, Thomas B.K., primary, McGranahan, Nicholas, primary, Kumar, Sacheen, primary, Abbassi-Ghadi, Nima, primary, Salm, Max, primary, Mitter, Richard, primary, Horswell, Stuart, primary, Rowan, Andrew, primary, Phillimore, Benjamin, primary, Biggs, Jennifer, primary, Begum, Sharmin, primary, Matthews, Nik, primary, Hochhauser, Daniel, primary, Hanna, George B., primary, and Swanton, Charles, primary

Published
2023
Full Text
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35. Data from MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy

Author

Neupane, Manish, primary, Clark, Allison P., primary, Landini, Serena, primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Lim, Elgene, primary, Culhane, Aedin C., primary, Barry, William T., primary, Schumacher, Steven E., primary, Beroukhim, Rameen, primary, Szallasi, Zoltan, primary, Vidal, Marc, primary, Hill, David E., primary, and Silver, Daniel P., primary

Published
2023
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36. Supplementary Methods, Tables S1 - S2, S4, Figures S1 - S11 from Tracking the Genomic Evolution of Esophageal Adenocarcinoma through Neoadjuvant Chemotherapy

Author

Murugaesu, Nirupa, primary, Wilson, Gareth A., primary, Birkbak, Nicolai J., primary, Watkins, Thomas B.K., primary, McGranahan, Nicholas, primary, Kumar, Sacheen, primary, Abbassi-Ghadi, Nima, primary, Salm, Max, primary, Mitter, Richard, primary, Horswell, Stuart, primary, Rowan, Andrew, primary, Phillimore, Benjamin, primary, Biggs, Jennifer, primary, Begum, Sharmin, primary, Matthews, Nik, primary, Hochhauser, Daniel, primary, Hanna, George B., primary, and Swanton, Charles, primary

Published
2023
Full Text
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37. Supplementary Methods from Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents

Author

Birkbak, Nicolai J., primary, Wang, Zhigang C., primary, Kim, Ji-Young, primary, Eklund, Aron C., primary, Li, Qiyuan, primary, Tian, Ruiyang, primary, Bowman-Colin, Christian, primary, Li, Yang, primary, Greene-Colozzi, April, primary, Iglehart, J. Dirk, primary, Tung, Nadine, primary, Ryan, Paula D., primary, Garber, Judy E., primary, Silver, Daniel P., primary, Szallasi, Zoltan, primary, and Richardson, Andrea L., primary

Published
2023
Full Text
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38. Supplementary Figures 1-7 from Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents

Author

Birkbak, Nicolai J., primary, Wang, Zhigang C., primary, Kim, Ji-Young, primary, Eklund, Aron C., primary, Li, Qiyuan, primary, Tian, Ruiyang, primary, Bowman-Colin, Christian, primary, Li, Yang, primary, Greene-Colozzi, April, primary, Iglehart, J. Dirk, primary, Tung, Nadine, primary, Ryan, Paula D., primary, Garber, Judy E., primary, Silver, Daniel P., primary, Szallasi, Zoltan, primary, and Richardson, Andrea L., primary

Published
2023
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41. Supplementary Tables 1-2 from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Author

Roylance, Rebecca, primary, Endesfelder, David, primary, Gorman, Patricia, primary, Burrell, Rebecca A., primary, Sander, Jil, primary, Tomlinson, Ian, primary, Hanby, Andrew M., primary, Speirs, Valerie, primary, Richardson, Andrea L., primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Downward, Julian, primary, Kschischo, Maik, primary, Szallasi, Zoltan, primary, and Swanton, Charles, primary

Published
2023
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42. Supplementary Figure 1 from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Author

Roylance, Rebecca, primary, Endesfelder, David, primary, Gorman, Patricia, primary, Burrell, Rebecca A., primary, Sander, Jil, primary, Tomlinson, Ian, primary, Hanby, Andrew M., primary, Speirs, Valerie, primary, Richardson, Andrea L., primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Downward, Julian, primary, Kschischo, Maik, primary, Szallasi, Zoltan, primary, and Swanton, Charles, primary

Published
2023
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43. Supplementary Figure 4 from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Author

Roylance, Rebecca, primary, Endesfelder, David, primary, Gorman, Patricia, primary, Burrell, Rebecca A., primary, Sander, Jil, primary, Tomlinson, Ian, primary, Hanby, Andrew M., primary, Speirs, Valerie, primary, Richardson, Andrea L., primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Downward, Julian, primary, Kschischo, Maik, primary, Szallasi, Zoltan, primary, and Swanton, Charles, primary

Published
2023
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44. Supplementary Figure Legends 1-4 from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Author

Roylance, Rebecca, primary, Endesfelder, David, primary, Gorman, Patricia, primary, Burrell, Rebecca A., primary, Sander, Jil, primary, Tomlinson, Ian, primary, Hanby, Andrew M., primary, Speirs, Valerie, primary, Richardson, Andrea L., primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Downward, Julian, primary, Kschischo, Maik, primary, Szallasi, Zoltan, primary, and Swanton, Charles, primary

Published
2023
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45. Supplementary Figure 2B from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Author

Roylance, Rebecca, primary, Endesfelder, David, primary, Gorman, Patricia, primary, Burrell, Rebecca A., primary, Sander, Jil, primary, Tomlinson, Ian, primary, Hanby, Andrew M., primary, Speirs, Valerie, primary, Richardson, Andrea L., primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Downward, Julian, primary, Kschischo, Maik, primary, Szallasi, Zoltan, primary, and Swanton, Charles, primary

Published
2023
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46. Supplementary Figure 3 from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Author

Roylance, Rebecca, primary, Endesfelder, David, primary, Gorman, Patricia, primary, Burrell, Rebecca A., primary, Sander, Jil, primary, Tomlinson, Ian, primary, Hanby, Andrew M., primary, Speirs, Valerie, primary, Richardson, Andrea L., primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Downward, Julian, primary, Kschischo, Maik, primary, Szallasi, Zoltan, primary, and Swanton, Charles, primary

Published
2023
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47. Supplementary Methods from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Author

Roylance, Rebecca, primary, Endesfelder, David, primary, Gorman, Patricia, primary, Burrell, Rebecca A., primary, Sander, Jil, primary, Tomlinson, Ian, primary, Hanby, Andrew M., primary, Speirs, Valerie, primary, Richardson, Andrea L., primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Downward, Julian, primary, Kschischo, Maik, primary, Szallasi, Zoltan, primary, and Swanton, Charles, primary

Published
2023
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48. Data from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Author

Roylance, Rebecca, primary, Endesfelder, David, primary, Gorman, Patricia, primary, Burrell, Rebecca A., primary, Sander, Jil, primary, Tomlinson, Ian, primary, Hanby, Andrew M., primary, Speirs, Valerie, primary, Richardson, Andrea L., primary, Birkbak, Nicolai J., primary, Eklund, Aron C., primary, Downward, Julian, primary, Kschischo, Maik, primary, Szallasi, Zoltan, primary, and Swanton, Charles, primary

Published
2023
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49. Data from Chromosomal Instability Confers Intrinsic Multidrug Resistance

Author

Lee, Alvin J.X., primary, Endesfelder, David, primary, Rowan, Andrew J., primary, Walther, Axel, primary, Birkbak, Nicolai J., primary, Futreal, P. Andrew, primary, Downward, Julian, primary, Szallasi, Zoltan, primary, Tomlinson, Ian P.M., primary, Howell, Michael, primary, Kschischo, Maik, primary, and Swanton, Charles, primary

Published
2023
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