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151. 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

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 TP53and 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 EGFRmutations and for RET, ROS1, ALKand METoncogenic 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.

Published
2023
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152. Lung adenocarcinoma promotion by air pollutants

Author

Hill, William, Lim, Emilia L., Weeden, Clare E., Lee, Claudia, Augustine, Marcellus, Chen, Kezhong, Kuan, Feng-Che, Marongiu, Fabio, Evans, Edward J., Moore, David A., Rodrigues, Felipe S., Pich, Oriol, Bakker, Bjorn, Cha, Hongui, Myers, Renelle, van Maldegem, Febe, Boumelha, Jesse, Veeriah, Selvaraju, Rowan, Andrew, Naceur-Lombardelli, Cristina, Karasaki, Takahiro, Sivakumar, Monica, De, Swapnanil, Caswell, Deborah R., Nagano, Ai, Black, James R. M., Martínez-Ruiz, Carlos, Ryu, Min Hyung, Huff, Ryan D., Li, Shijia, Favé, Marie-Julie, Magness, Alastair, Suárez-Bonnet, Alejandro, Priestnall, Simon L., Lüchtenborg, Margreet, Lavelle, Katrina, Pethick, Joanna, Hardy, Steven, McRonald, Fiona E., Lin, Meng-Hung, Troccoli, Clara I., Ghosh, Moumita, Miller, York E., Merrick, Daniel T., Keith, Robert L., Al Bakir, Maise, Bailey, Chris, Hill, Mark S., Saal, Lao H., Chen, Yilun, George, Anthony M., Abbosh, Christopher, Kanu, Nnennaya, Lee, Se-Hoon, McGranahan, Nicholas, Berg, Christine D., Sasieni, Peter, Houlston, Richard, Turnbull, Clare, Lam, Stephen, Awadalla, Philip, Grönroos, Eva, Downward, Julian, Jacks, Tyler, Carlsten, Christopher, Malanchi, Ilaria, Hackshaw, Allan, Litchfield, Kevin, DeGregori, James, Jamal-Hanjani, Mariam, and Swanton, Charles

Abstract

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFRand KRASdriver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM2.5air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

Published
2023
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153. 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

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 MAGEA6and 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.

Published
2023
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154. 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

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 SMARCA4gene 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.

Published
2023
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155. The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner

Author

Meinhardt, Anna-Lena, Munkhbaatar, Enkhtsetseg, H��ckendorf, Ulrike, Dietzen, Michelle, Dechant, Marta, Anton, Martina, Jacob, Anne, Steiger, Katja, Weichert, Wilko, Brcic, Luka, McGranahan, Nicholas, Branca, Caterina, Kaufmann, Thomas, Dengler, Michael A, and Jost, Philipp J

Subjects
Cancer Research, ComputingMethodologies_PATTERNRECOGNITION, Genetics, 610 Medicine & health, Tumor Suppressor Protein p53, Molecular Biology
Abstract

A variety of cancer entities are driven by KRAS mutations, which remain difficult to target clinically. Survival pathways, such as resistance to cell death, may represent a promising treatment approach in KRAS mutated cancers. Based on the frequently observed genomic deletions of BCL-2-related ovarian killer (BOK) in cancer patients, we explored the function of BOK in a mutant KrasG12D-driven murine model of lung cancer. Using KrasG12D/+Bok−/− mice, we observed an overall tumor-promoting function of BOK in vivo. Specifically, loss of BOK reduced proliferation both in cell lines in vitro as well as in KrasG12D-driven tumor lesions in vivo. During tumor development in vivo, loss of BOK resulted in a lower tumor burden, with fewer, smaller, and less advanced tumors. Using KrasG12D/+Tp53Δ/ΔBok−/− mice, we identified that this phenotype was entirely dependent on the presence of functional p53. Furthermore, analysis of a human dataset of untreated early-stage lung tumors did not identify any common deletion of the BOK locus, independently of the TP53 status or the histopathological classification. Taken together our data indicate that BOK supports tumor progression in Kras-driven lung cancer.

Published
2021

156. The causes and consequences of genetic heterogeneity in cancer evolution

Author

Burrell, Rebecca A., McGranahan, Nicholas, Bartek, Jiri, and Swanton, Charles

Subjects
Cancer -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Recent studies have revealed extensive genetic diversity both between and within tumours. This heterogeneity affects key cancer pathways, driving phenotypic variation, and poses a significant challenge to personalized cancer medicine. A major cause of genetic heterogeneity in cancer is genomic instability. This instability leads to an increased mutation rate and can shape the evolution of the cancer genome through a plethora of mechanisms. By understanding these mechanisms we can gain insight into the common pathways of tumour evolution that could support the development of future therapeutic strategies., Extensive genetic and phenotypic variation exist not only between tumours (intertumour heterogeneity) but also within individual tumours (intratumour heterogeneity; Fig. 1). In tumours, populations of genetically distinct subclones can intermingle [...]

Published
2013
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157. Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Author

Memon, Danish, primary, Rizvi, Hira, additional, Fromm, George, additional, Lihm, Jayon, additional, Schoenfeld, Adam J., additional, Sauter, Jennifer L., additional, Luo, Jia, additional, Chow, Andrew, additional, Bhanot, Umesh K., additional, McCarthy, Caroline, additional, Ye, Darwin, additional, Vanderbilt, Chad M., additional, Liu, Cailian, additional, Abu-Akeel, Mohsen, additional, Plodkowski, Andrew J., additional, McGranahan, Nicholas, additional, Łuksza, Marta, additional, Greenbaum, Benjamin D., additional, Merghoub, Taha, additional, Minn, Andy J., additional, Beltrao, Pedro, additional, Schreiber, Taylor H., additional, Miller, Martin L., additional, and Hellmann, Matthew D., additional

Published
2021
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158. Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

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

Subjects
viruses
Abstract

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non-small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G(1) phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. SIGNIFICANCE : This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution.

Published
2021

159. Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Author

Memon, Danish, Rizvi, Hira, Fromm, George, Lihm, Jayon, Schoenfeld, Adam J., Sauter, Jennifer L., Luo, Jia, Chow, Andrew, Bhanot, Umesh K., McCarthy, Caroline, Ye, Darwin, Vanderbilt, Chad M., Liu, Cailian, Abu-Akeel, Mohsen, Plodkowski, Andrew J., McGranahan, Nicholas, Luksza, Marta, Greenbaum, Benjamin D., Merghoub, Taha, Minn, Andy J., Beltrao, Pedro, Schreiber, Taylor H., Miller, Martin L., and Hellmann, Matthew D.

Abstract

Although cancer immunotherapy with PD-(L)1 blockade is now routine treatment for patients with lung cancer, remarkably little is known about acquired resistance. We examined 1,201 patients with NSCLC treated with PD-(L)1 blockade to clinically characterize acquired resistance, finding it to be common (occurring in more than 60% of initial responders), with persistent but diminishing risk over time, and with distinct metastatic and survival patterns compared to primary resistance. To examine the molecular phenotype and potential mechanisms of acquired resistance, we performed whole transcriptome and exome tumor profiling in a subset of NSCLC patients (n=29) with acquired resistance. Systematic immunogenomic analysis revealed that tumors with acquired resistance generally had enriched signals of inflammation (including IFNγ signaling and inferred CD8+ T cells) and could be separated into IFNγ upregulated and stable subsets. IFNγ upregulated tumors had putative routes of resistance with signatures of dysfunctional interferon signaling and mutations in antigen presentation genes. Transcriptomic profiling of cancer cells from a murine model of acquired resistance to PD-(L)1 blockade also showed evidence of dysfunctional interferon signaling and acquired insensitivity to in vitro interferon gamma treatment. In summary, we characterized clinical and molecular features of acquired resistance to PD-(L)1 blockade in NSCLC and found evidence of ongoing but dysfunctional IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance., bioRxiv

Published
2021
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160. Identifying key questions in the ecology and evolution of cancer.

Author

Dujon, Antoine M, Dujon, Antoine M, Aktipis, Athena, Alix-Panabières, Catherine, Amend, Sarah R, Boddy, Amy M, Brown, Joel S, Capp, Jean-Pascal, DeGregori, James, Ewald, Paul, Gatenby, Robert, Gerlinger, Marco, Giraudeau, Mathieu, Hamede, Rodrigo K, Hansen, Elsa, Kareva, Irina, Maley, Carlo C, Marusyk, Andriy, McGranahan, Nicholas, Metzger, Michael J, Nedelcu, Aurora M, Noble, Robert, Nunney, Leonard, Pienta, Kenneth J, Polyak, Kornelia, Pujol, Pascal, Read, Andrew F, Roche, Benjamin, Sebens, Susanne, Solary, Eric, Staňková, Kateřina, Swain Ewald, Holly, Thomas, Frédéric, Ujvari, Beata, Dujon, Antoine M, Dujon, Antoine M, Aktipis, Athena, Alix-Panabières, Catherine, Amend, Sarah R, Boddy, Amy M, Brown, Joel S, Capp, Jean-Pascal, DeGregori, James, Ewald, Paul, Gatenby, Robert, Gerlinger, Marco, Giraudeau, Mathieu, Hamede, Rodrigo K, Hansen, Elsa, Kareva, Irina, Maley, Carlo C, Marusyk, Andriy, McGranahan, Nicholas, Metzger, Michael J, Nedelcu, Aurora M, Noble, Robert, Nunney, Leonard, Pienta, Kenneth J, Polyak, Kornelia, Pujol, Pascal, Read, Andrew F, Roche, Benjamin, Sebens, Susanne, Solary, Eric, Staňková, Kateřina, Swain Ewald, Holly, Thomas, Frédéric, and Ujvari, Beata

Abstract

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer.

Published
2021

161. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Author

Dentro, Stefan C, Dentro, Stefan C, Leshchiner, Ignaty, Haase, Kerstin, Tarabichi, Maxime, Wintersinger, Jeff, Deshwar, Amit G, Yu, Kaixian, Rubanova, Yulia, Macintyre, Geoff, Demeulemeester, Jonas, Vázquez-García, Ignacio, Kleinheinz, Kortine, Livitz, Dimitri G, Malikic, Salem, Donmez, Nilgun, Sengupta, Subhajit, Anur, Pavana, Jolly, Clemency, Cmero, Marek, Rosebrock, Daniel, Schumacher, Steven E, Fan, Yu, Fittall, Matthew, Drews, Ruben M, Yao, Xiaotong, Watkins, Thomas BK, Lee, Juhee, Schlesner, Matthias, Zhu, Hongtu, Adams, David J, McGranahan, Nicholas, Swanton, Charles, Getz, Gad, Boutros, Paul C, Imielinski, Marcin, Beroukhim, Rameen, Sahinalp, S Cenk, Ji, Yuan, Peifer, Martin, Martincorena, Inigo, Markowetz, Florian, Mustonen, Ville, Yuan, Ke, Gerstung, Moritz, Spellman, Paul T, Wang, Wenyi, Morris, Quaid D, Wedge, David C, Van Loo, Peter, PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium, Dentro, Stefan C, Dentro, Stefan C, Leshchiner, Ignaty, Haase, Kerstin, Tarabichi, Maxime, Wintersinger, Jeff, Deshwar, Amit G, Yu, Kaixian, Rubanova, Yulia, Macintyre, Geoff, Demeulemeester, Jonas, Vázquez-García, Ignacio, Kleinheinz, Kortine, Livitz, Dimitri G, Malikic, Salem, Donmez, Nilgun, Sengupta, Subhajit, Anur, Pavana, Jolly, Clemency, Cmero, Marek, Rosebrock, Daniel, Schumacher, Steven E, Fan, Yu, Fittall, Matthew, Drews, Ruben M, Yao, Xiaotong, Watkins, Thomas BK, Lee, Juhee, Schlesner, Matthias, Zhu, Hongtu, Adams, David J, McGranahan, Nicholas, Swanton, Charles, Getz, Gad, Boutros, Paul C, Imielinski, Marcin, Beroukhim, Rameen, Sahinalp, S Cenk, Ji, Yuan, Peifer, Martin, Martincorena, Inigo, Markowetz, Florian, Mustonen, Ville, Yuan, Ke, Gerstung, Moritz, Spellman, Paul T, Wang, Wenyi, Morris, Quaid D, Wedge, David C, Van Loo, Peter, and PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium

Abstract

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

Published
2021

162. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Author

Dentro, Stefan C., Leshchiner, Ignaty, Haase, Kerstin, Tarabichi, Maxime, Wintersinger, Jeff, Deshwar, Amit G., Yu, Kaixian, Rubanova, Yulia, Macintyre, Geoff, Demeulemeester, Jonas, Vazquez-Garcia, Ignacio, Kleinheinz, Kortine, Livitz, Dimitri G., Malikic, Salem, Donmez, Nilgun, Sengupta, Subhajit, Anur, Pavana, Jolly, Clemency, Cmero, Marek, Rosebrock, Daniel, Schumacher, Steven E., Fan, Yu, Fittall, Matthew, Drews, Ruben M., Yao, Xiaotong, Watkins, Thomas B. K., Lee, Juhee, Schlesner, Matthias, Zhu, Hongtu, Adams, David J., McGranahan, Nicholas, Swanton, Charles, Getz, Gad, Boutros, Paul C., Imielinski, Marcin, Beroukhim, Rameen, Sahinalp, S. Cenk, Ji, Yuan, Peifer, Martin, Martincorena, Inigo, Markowetz, Florian, Mustonen, Ville, Yuan, Ke, Gerstung, Moritz, Spellman, Paul T., Wang, Wenyi, Morris, Quaid D., Wedge, David C., Van Loo, Peter, Dentro, Stefan C., Leshchiner, Ignaty, Haase, Kerstin, Tarabichi, Maxime, Wintersinger, Jeff, Deshwar, Amit G., Yu, Kaixian, Rubanova, Yulia, Macintyre, Geoff, Demeulemeester, Jonas, Vazquez-Garcia, Ignacio, Kleinheinz, Kortine, Livitz, Dimitri G., Malikic, Salem, Donmez, Nilgun, Sengupta, Subhajit, Anur, Pavana, Jolly, Clemency, Cmero, Marek, Rosebrock, Daniel, Schumacher, Steven E., Fan, Yu, Fittall, Matthew, Drews, Ruben M., Yao, Xiaotong, Watkins, Thomas B. K., Lee, Juhee, Schlesner, Matthias, Zhu, Hongtu, Adams, David J., McGranahan, Nicholas, Swanton, Charles, Getz, Gad, Boutros, Paul C., Imielinski, Marcin, Beroukhim, Rameen, Sahinalp, S. Cenk, Ji, Yuan, Peifer, Martin, Martincorena, Inigo, Markowetz, Florian, Mustonen, Ville, Yuan, Ke, Gerstung, Moritz, Spellman, Paul T., Wang, Wenyi, Morris, Quaid D., Wedge, David C., and Van Loo, Peter

Abstract

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1 %) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones, We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

Published
2021

163. Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer

Author

Chen, Ming, Chen, Runzhe, Jin, Ying, Li, Jun, Hu, Xin, Zhang, Jiexin, Fujimoto, Junya, Hubert, Shawna M., Gay, Carl M., Zhu, Bo, Tian, Yanhua, McGranahan, Nicholas, Lee, Won-Chul, George, Julie, Hu, Xiao, Chen, Yamei, Wu, Meijuan, Behrens, Carmen, Chow, Chi-Wan, Pham, Hoa H. N., Fukuoka, Junya, Wu, Jia, Parra, Edwin Roger, Little, Latasha D., Gumbs, Curtis, Song, Xingzhi, Wu, Chang-Jiun, Diao, Lixia, Wang, Qi, Cardnell, Robert, Zhang, Jianhua, Wang, Jing, Le, Xiuning, Gibbons, Don L., Heymach, John, V, Lee, J. Jack, William, William N., Jr., Cheng, Chao, Glisson, Bonnie, Wistuba, Ignacio, Futreal, P. Andrew, Thomas, Roman K., Reuben, Alexandre, Byers, Lauren A., Zhang, Jianjun, Chen, Ming, Chen, Runzhe, Jin, Ying, Li, Jun, Hu, Xin, Zhang, Jiexin, Fujimoto, Junya, Hubert, Shawna M., Gay, Carl M., Zhu, Bo, Tian, Yanhua, McGranahan, Nicholas, Lee, Won-Chul, George, Julie, Hu, Xiao, Chen, Yamei, Wu, Meijuan, Behrens, Carmen, Chow, Chi-Wan, Pham, Hoa H. N., Fukuoka, Junya, Wu, Jia, Parra, Edwin Roger, Little, Latasha D., Gumbs, Curtis, Song, Xingzhi, Wu, Chang-Jiun, Diao, Lixia, Wang, Qi, Cardnell, Robert, Zhang, Jianhua, Wang, Jing, Le, Xiuning, Gibbons, Don L., Heymach, John, V, Lee, J. Jack, William, William N., Jr., Cheng, Chao, Glisson, Bonnie, Wistuba, Ignacio, Futreal, P. Andrew, Thomas, Roman K., Reuben, Alexandre, Byers, Lauren A., and Zhang, Jianjun

Abstract

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-gamma pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC. Small-cell lung cancer (SCLC) is an aggressive disease with limited therapeutic options. Here the authors perform an immunogenomic analysis of limited-stage SCLC, revealing a homogeneous mutational landscape, but limited T-cell infiltration and a cold and heterogeneous T cell repertoire.

Published
2021

164. Induction of APOBEC3 exacerbates DNA replication stress and chromosomal instability in early breast and lung cancer evolution

Author

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

Abstract

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast DCIS, and in pre-invasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx pre-invasive to invasive NSCLC lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models, revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in pre-invasive disease, providing fuel for selection early in cancer evolution.

Published
2021

165. Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

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

Abstract

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non–small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. Significance: This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution

Published
2021

166. DeCiFering the subclonal composition of tumors

Author

Yan, Haixi, Tarabichi, Maxime, McGranahan, Nicholas, Van Loo, Peter, Yan, Haixi, Tarabichi, Maxime, McGranahan, Nicholas, and Van Loo, Peter

Abstract

Accurately identifying the subclones that make up tumors is critical for understanding cancer biology. In an article in this issue of Cell Systems, Satas et al. examine mutations with an evolutionary perspective to decipher the composition of tumors., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2021

167. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Author

Litchfield, Kevin, Reading, James L., Puttick, Clare, Thakkar, Krupa, Abbosh, Chris, Bentham, Robert, Watkins, Thomas B.K., Rosenthal, Rachel, Biswas, Dhruva, Rowan, Andrew, Lim, Emilia, Al Bakir, Maise, Turati, Virginia, Guerra-Assunção, José Afonso, Conde, Lucia, Furness, Andrew J.S., Saini, Sunil Kumar, Hadrup, Sine R., Herrero, Javier, Lee, Se Hoon, Van Loo, Peter, Enver, Tariq, Larkin, James, Hellmann, Matthew D., Turajlic, Samra, Quezada, Sergio A., McGranahan, Nicholas, Swanton, Charles, Litchfield, Kevin, Reading, James L., Puttick, Clare, Thakkar, Krupa, Abbosh, Chris, Bentham, Robert, Watkins, Thomas B.K., Rosenthal, Rachel, Biswas, Dhruva, Rowan, Andrew, Lim, Emilia, Al Bakir, Maise, Turati, Virginia, Guerra-Assunção, José Afonso, Conde, Lucia, Furness, Andrew J.S., Saini, Sunil Kumar, Hadrup, Sine R., Herrero, Javier, Lee, Se Hoon, Van Loo, Peter, Enver, Tariq, Larkin, James, Hellmann, Matthew D., Turajlic, Samra, Quezada, Sergio A., McGranahan, Nicholas, and Swanton, Charles

Abstract

Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.

Published
2021

169. LUNG CANCER EVOLUTION: Spatial and temporal diversity in genomic instability processes defines lung cancer evolution

Author

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

Published
2014
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170. 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

Abstract

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.

Published
2023
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171. Author Correction: Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma

Author

Hu, Xin, primary, Fujimoto, Junya, additional, Ying, Lisha, additional, Fukuoka, Junya, additional, Ashizawa, Kazuto, additional, Sun, Wenyong, additional, Reuben, Alexandre, additional, Chow, Chi-Wan, additional, McGranahan, Nicholas, additional, Chen, Runzhe, additional, Hu, Jinlin, additional, Godoy, Myrna C., additional, Tabata, Kazuhiro, additional, Kuroda, Kishio, additional, Shi, Lei, additional, Li, Jun, additional, Behrens, Carmen, additional, Parra, Edwin Roger, additional, Little, Latasha D., additional, Gumbs, Curtis, additional, Mao, Xizeng, additional, Song, Xingzhi, additional, Tippen, Samantha, additional, Thornton, Rebecca L., additional, Kadara, Humam, additional, Scheet, Paul, additional, Roarty, Emily, additional, Ostrin, Edwin Justin, additional, Wang, Xu, additional, Carter, Brett W., additional, Antonoff, Mara B., additional, Zhang, Jianhua, additional, Vaporciyan, Ara A., additional, Pass, Harvey, additional, Swisher, Stephen G., additional, Heymach, John V., additional, Lee, J. Jack, additional, Wistuba, Ignacio I., additional, Hong, Waun Ki, additional, Futreal, P. Andrew, additional, Su, Dan, additional, and Zhang, Jianjun, additional

Published
2021
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172. Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

Author

Dejima, Hitoshi, primary, Hu, Xin, additional, Chen, Runzhe, additional, Zhang, Jiexin, additional, Fujimoto, Junya, additional, Parra, Edwin R., additional, Haymaker, Cara, additional, Hubert, Shawna M., additional, Duose, Dzifa, additional, Solis, Luisa M., additional, Su, Dan, additional, Fukuoka, Junya, additional, Tabata, Kazuhiro, additional, Pham, Hoa H. N., additional, Mcgranahan, Nicholas, additional, Zhang, Baili, additional, Ye, Jie, additional, Ying, Lisha, additional, Little, Latasha, additional, Gumbs, Curtis, additional, Chow, Chi-Wan, additional, Estecio, Marcos Roberto, additional, Godoy, Myrna C. B., additional, Antonoff, Mara B., additional, Sepesi, Boris, additional, Pass, Harvey I., additional, Behrens, Carmen, additional, Zhang, Jianhua, additional, Vaporciyan, Ara A., additional, Heymach, John V., additional, Scheet, Paul, additional, Lee, J. Jack, additional, Wu, Jia, additional, Futreal, P. Andrew, additional, Reuben, Alexandre, additional, Kadara, Humam, additional, Wistuba, Ignacio I., additional, and Zhang, Jianjun, additional

Published
2021
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173. Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

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

Published
2021
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174. Tracking Cancer Evolution through the Disease Course

Author

Bailey, Chris, primary, Black, James R.M., additional, Reading, James L., additional, Litchfield, Kevin, additional, Turajlic, Samra, additional, McGranahan, Nicholas, additional, Jamal-Hanjani, Mariam, additional, and Swanton, Charles, additional

Published
2021
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175. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Author

Dentro, Stefan C., primary, Leshchiner, Ignaty, additional, Haase, Kerstin, additional, Tarabichi, Maxime, additional, Wintersinger, Jeff, additional, Deshwar, Amit G., additional, Yu, Kaixian, additional, Rubanova, Yulia, additional, Macintyre, Geoff, additional, Demeulemeester, Jonas, additional, Vázquez-García, Ignacio, additional, Kleinheinz, Kortine, additional, Livitz, Dimitri G., additional, Malikic, Salem, additional, Donmez, Nilgun, additional, Sengupta, Subhajit, additional, Anur, Pavana, additional, Jolly, Clemency, additional, Cmero, Marek, additional, Rosebrock, Daniel, additional, Schumacher, Steven E., additional, Fan, Yu, additional, Fittall, Matthew, additional, Drews, Ruben M., additional, Yao, Xiaotong, additional, Watkins, Thomas B.K., additional, Lee, Juhee, additional, Schlesner, Matthias, additional, Zhu, Hongtu, additional, Adams, David J., additional, McGranahan, Nicholas, additional, Swanton, Charles, additional, Getz, Gad, additional, Boutros, Paul C., additional, Imielinski, Marcin, additional, Beroukhim, Rameen, additional, Sahinalp, S. Cenk, additional, Ji, Yuan, additional, Peifer, Martin, additional, Martincorena, Inigo, additional, Markowetz, Florian, additional, Mustonen, Ville, additional, Yuan, Ke, additional, Gerstung, Moritz, additional, Spellman, Paul T., additional, Wang, Wenyi, additional, Morris, Quaid D., additional, Wedge, David C., additional, Van Loo, Peter, additional, Dentro, Stefan C., additional, Gonzalez, Santiago, additional, Bowtell, David D., additional, Campbell, Peter J., additional, Cao, Shaolong, additional, Christie, Elizabeth L., additional, Cun, Yupeng, additional, Dawson, Kevin J., additional, Eils, Roland, additional, Garsed, Dale W., additional, Ha, Gavin, additional, Jerman, Lara, additional, Lee-Six, Henry, additional, Mitchell, Thomas J., additional, Oesper, Layla, additional, Peto, Myron, additional, Raphael, Benjamin J., additional, Salcedo, Adriana, additional, Shi, Ruian, additional, Shin, Seung Jun, additional, Stein, Lincoln D., additional, Spiro, Oliver, additional, Vembu, Shankar, additional, Wheeler, David A., additional, and Yang, Tsun-Po, additional

Published
2021
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176. Promises and challenges of adoptive T-cell therapies for solid tumours

Author

Morotti, Matteo, primary, Albukhari, Ashwag, additional, Alsaadi, Abdulkhaliq, additional, Artibani, Mara, additional, Brenton, James D., additional, Curbishley, Stuart M., additional, Dong, Tao, additional, Dustin, Michael L., additional, Hu, Zhiyuan, additional, McGranahan, Nicholas, additional, Miller, Martin L., additional, Santana-Gonzalez, Laura, additional, Seymour, Leonard W., additional, Shi, Tingyan, additional, Van Loo, Peter, additional, Yau, Christopher, additional, White, Helen, additional, Wietek, Nina, additional, Church, David N., additional, Wedge, David C., additional, and Ahmed, Ahmed A., additional

Published
2021
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181. 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, Lund, Tom, Moore, David A., Salgado, Roberto, Al Bakir, Maise, Zapata, Luis, Hiley, Crispin T., Officer, Leah, Sereno, Marco, Smith, Claire Rachel, Loi, Sherene, Hackshaw, Allan, Marafioti, Teresa, Quezada, Sergio A., McGranahan, Nicholas, Le Quesne, John, Swanton, Charles, Yuan, Yinyin, Blyth, Kevin G., Dick, Craig, and Kidd, Andrew

Abstract

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape1,2,3,4,5. 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 cohort6. 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.

Published
2020

182. Additional file 3 of Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Author

Won-Chul Lee, Reuben, Alexandre, Hu, Xin, McGranahan, Nicholas, Runzhe Chen, Jalali, Ali, Negrao, Marcelo V., Hubert, Shawna M., Tang, Chad, Chia-Chin Wu, Lucas, Anthony San, Whijae Roh, Suda, Kenichi, Jihye Kim, Aik-Choon Tan, Peng, David H., Lu, Wei, Ximing Tang, Chi-Wan Chow, Fujimoto, Junya, Behrens, Carmen, Kalhor, Neda, Fukumura, Kazutaka, Coyle, Marcus, Thornton, Rebecca, Gumbs, Curtis, Li, Jun, Chang-Jiun Wu, Little, Latasha, Roarty, Emily, Xingzhi Song, J. Jack Lee, Sulman, Erik P., Rao, Ganesh, Swisher, Stephen, Lixia Diao, Wang, Jing, Heymach, John V., Huse, Jason T., Scheet, Paul, Wistuba, Ignacio I., Gibbons, Don L., P. Andrew Futreal, Jianhua Zhang, Gomez, Daniel, and Jianjun Zhang

Abstract

Additional file 3: Review history.

Published
2020
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183. Additional file 2 of Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Author

Won-Chul Lee, Reuben, Alexandre, Hu, Xin, McGranahan, Nicholas, Runzhe Chen, Jalali, Ali, Negrao, Marcelo V., Hubert, Shawna M., Tang, Chad, Chia-Chin Wu, Lucas, Anthony San, Whijae Roh, Suda, Kenichi, Jihye Kim, Aik-Choon Tan, Peng, David H., Lu, Wei, Ximing Tang, Chi-Wan Chow, Fujimoto, Junya, Behrens, Carmen, Kalhor, Neda, Fukumura, Kazutaka, Coyle, Marcus, Thornton, Rebecca, Gumbs, Curtis, Li, Jun, Chang-Jiun Wu, Little, Latasha, Roarty, Emily, Xingzhi Song, J. Jack Lee, Sulman, Erik P., Rao, Ganesh, Swisher, Stephen, Lixia Diao, Wang, Jing, Heymach, John V., Huse, Jason T., Scheet, Paul, Wistuba, Ignacio I., Gibbons, Don L., P. Andrew Futreal, Jianhua Zhang, Gomez, Daniel, and Jianjun Zhang

Abstract

Additional file 2: Supplementary Figs. S1-S22.

Published
2020
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184. Pervasive chromosomal instability and karyotype order in tumour evolution.

Author

Watkins, Thomas BK, 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, Swanton, Charles, Watkins, Thomas BK, 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

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

185. The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Author

Ghorani, Ehsan, Reading, James L, Henry, Jake Y, de Massy, Marc Robert, Rosenthal, Rachel, Turati, Virginia, Joshi, Kroopa, Furness, Andrew J S, Aissa, Assma Ben, Saini, Sunil Kumar, Ramskov, Sofie, Georgiou, Andrew, Sunderland, Mariana Werner, Wong, Yien Ning Sophia, De Mucha, Maria Vila, Day, William, Galvez-Cancino, Felipe, Becker, Pablo D, Uddin, Imran, 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, Al Bakir, Maise, 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, Quezada, Sergio A, Ghorani, Ehsan, Reading, James L, Henry, Jake Y, de Massy, Marc Robert, Rosenthal, Rachel, Turati, Virginia, Joshi, Kroopa, Furness, Andrew J S, Aissa, Assma Ben, Saini, Sunil Kumar, Ramskov, Sofie, Georgiou, Andrew, Sunderland, Mariana Werner, Wong, Yien Ning Sophia, De Mucha, Maria Vila, Day, William, Galvez-Cancino, Felipe, Becker, Pablo D, Uddin, Imran, 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, Al Bakir, Maise, 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

Abstract

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.

Published
2020

187. Identifying key questions in the ecology and evolution of cancer

Author

Dujon, Antoine M., primary, Aktipis, Athena, additional, Alix‐Panabières, Catherine, additional, Amend, Sarah R., additional, Boddy, Amy M., additional, Brown, Joel S., additional, Capp, Jean‐Pascal, additional, DeGregori, James, additional, Ewald, Paul, additional, Gatenby, Robert, additional, Gerlinger, Marco, additional, Giraudeau, Mathieu, additional, Hamede, Rodrigo K., additional, Hansen, Elsa, additional, Kareva, Irina, additional, Maley, Carlo C., additional, Marusyk, Andriy, additional, McGranahan, Nicholas, additional, Metzger, Michael J., additional, Nedelcu, Aurora M., additional, Noble, Robert, additional, Nunney, Leonard, additional, Pienta, Kenneth J., additional, Polyak, Kornelia, additional, Pujol, Pascal, additional, Read, Andrew F., additional, Roche, Benjamin, additional, Sebens, Susanne, additional, Solary, Eric, additional, Staňková, Kateřina, additional, Swain Ewald, Holly, additional, Thomas, Frédéric, additional, and Ujvari, Beata, additional

Published
2021
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188. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Author

Litchfield, Kevin, primary, Reading, James L., additional, Puttick, Clare, additional, Thakkar, Krupa, additional, Abbosh, Chris, additional, Bentham, Robert, additional, Watkins, Thomas B.K., additional, Rosenthal, Rachel, additional, Biswas, Dhruva, additional, Rowan, Andrew, additional, Lim, Emilia, additional, Al Bakir, Maise, additional, Turati, Virginia, additional, Guerra-Assunção, José Afonso, additional, Conde, Lucia, additional, Furness, Andrew J.S., additional, Saini, Sunil Kumar, additional, Hadrup, Sine R., additional, Herrero, Javier, additional, Lee, Se-Hoon, additional, Van Loo, Peter, additional, Enver, Tariq, additional, Larkin, James, additional, Hellmann, Matthew D., additional, Turajlic, Samra, additional, Quezada, Sergio A., additional, McGranahan, Nicholas, additional, and Swanton, Charles, additional

Published
2021
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189. Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

Author

Hu, Xin, primary, Estecio, Marcos R., additional, Chen, Runzhe, additional, Reuben, Alexandre, additional, Wang, Linghua, additional, Fujimoto, Junya, additional, Carrot-Zhang, Jian, additional, McGranahan, Nicholas, additional, Ying, Lisha, additional, Fukuoka, Junya, additional, Chow, Chi-Wan, additional, Pham, Hoa H. N., additional, Godoy, Myrna C. B., additional, Carter, Brett W., additional, Behrens, Carmen, additional, Zhang, Jianhua, additional, Antonoff, Mara B., additional, Sepesi, Boris, additional, Lu, Yue, additional, Pass, Harvey I., additional, Kadara, Humam, additional, Scheet, Paul, additional, Vaporciyan, Ara A., additional, Heymach, John V., additional, Wistuba, Ignacio I., additional, Lee, J. Jack, additional, Futreal, P. Andrew, additional, Su, Dan, additional, Issa, Jean-Pierre J., additional, and Zhang, Jianjun, additional

Published
2021
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190. Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Author

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

Published
2020
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191. Publisher Correction: Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse

Author

Chemi, Francesca, Rothwell, Dominic G., McGranahan, Nicholas, Gulati, Sakshi, Abbosh, Chris, Pearce, Simon P., and Zhou, Cong

Subjects
Biological sciences, Health
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Francesca Chemi [sup.1] [sup.2] , Dominic G. Rothwell [sup.1] , Nicholas McGranahan [sup.3] [sup.4] [sup.5] , Sakshi Gulati [sup.1] , Chris Abbosh [sup.4] , Simon P. Pearce [sup.1] , [...]

Published
2020
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193. Copy number-aware deconvolution of tumor-normal DNA methylation profiles

Author

Cadieux, Elizabeth Larose, primary, Tanić, Miljana, additional, Wilson, Gareth A., additional, Baker, Toby, additional, Dietzen, Michelle, additional, Dhami, Pawan, additional, Vaikkinen, Heli, additional, Watkins, Thomas B. K., additional, Kanu, Nnennaya, additional, Veeriah, Selvaraju, additional, Jamal-Hanjani, Mariam, additional, McGranahan, Nicholas, additional, Feber, Andrew, additional, Swanton, Charles, additional, Beck, Stephan, additional, Demeulemeester, Jonas, additional, and Van Loo, Peter, additional

Published
2020
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194. Somatic chromosomal number alterations affecting driver genes inform in-vitro and clinical drug response in high-grade serous ovarian cancer

Author

Martins, Filipe Correia, primary, Couturier, Dominique-Laurent, additional, Santiago, Ines de, additional, Sauer, Carolin Margarethe, additional, Vias, Maria, additional, Angelova, Mihaela, additional, Sanders, Deborah, additional, Piskorz, Anna, additional, Hall, James, additional, Hosking, Karen, additional, Amirthanayagam, Anumithra, additional, Cosulich, Sabina, additional, Carnevalli, Larissa, additional, Davies, Barry, additional, Watkins, Tom B. K., additional, Funingana, Gabriel, additional, Bolton, Helen, additional, Haldar, Krishnayan, additional, Latimer, John, additional, Baldwin, Peter, additional, Crawford, Robin, additional, Eldridge, Matthew, additional, Basu, Bristi, additional, Jimenez-Linan, Mercedes, additional, McGranahan, Nicholas, additional, Litchfield, Kevin, additional, Shah, Sohrab P., additional, McNeish, Iain, additional, Caldas, Carlos, additional, Evan, Gerard, additional, Swanton, Charles, additional, and Brenton, James D., additional

Published
2020
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195. Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer

Author

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

Published
2020
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196. Meta-analysis of tumor and T cell intrinsic mechanisms of sensitization to checkpoint inhibition

Author

Litchfield, Kevin, primary, Reading, James L., additional, Puttick, Clare, additional, Abbosh, Chris, additional, Bentham, Robert, additional, Watkins, Thomas B. K., additional, Rosenthal, Rachel, additional, Biswas, Dhruva, additional, Lim, Emilia, additional, AL-Bakir, Maise, additional, Turati, Virginia, additional, Guerra-Assunção, José Afonso, additional, Conde, Lucia, additional, Furness, Andrew J.S., additional, Saini, Sunil Kumar, additional, Hadrup, Sine R, additional, Herrero, Javier, additional, Rowan, Andrew, additional, Enver, Tariq, additional, Hellmann, Matthew D., additional, Larkin, James, additional, Turajlic, Samra, additional, Quezada, Sergio, additional, McGranahan, Nicholas, additional, and Swanton, Charles, additional

Published
2020
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197. Pervasive chromosomal instability and karyotype order in tumour evolution

Author

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

Published
2020
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198. Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

Author

Dejima, Hitoshi, primary, Hu, Xin, additional, Chen, Runzhe, additional, Zhang, Jiexin, additional, Fujimoto, Junya, additional, Parra, Edwin R., additional, Haymaker, Cara, additional, Hubert, Shawna, additional, Duose, Dzifa, additional, Solis, Luisa M., additional, Su, Dan, additional, Fukuoka, Junya, additional, Tabata, Kazuhiro, additional, Pharm, Hoa, additional, Mcgranahan, Nicholas, additional, Zhang, Baili, additional, Ye, Jie, additional, Ying, Lisha, additional, Little, Latasha, additional, Gumbs, Curtis, additional, Chow, Chi-Wan, additional, Estecio, Marcos Roberto, additional, Godoy, Myrna C.B., additional, Antonoff, Mara B., additional, Sepesi, Boris, additional, Pass, Harvey, additional, Behrens, Carmen, additional, Zhang, Jianhua, additional, Vaporciyan, Ara A., additional, Heymach, John V., additional, Scheet, Paul, additional, Lee, J. Jack, additional, Futreal, P. Andrew, additional, Reuben, Alexandre, additional, Kadara, Humam, additional, Wistuba, Ignacio, additional, and Zhang, Jianjun, additional

Published
2020
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199. Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

Author

Hu, Xin, primary, Estecio, Marcos R., additional, Chen, Runzhe, additional, Reuben, Alexandre, additional, Wang, Linghua, additional, Fujimoto, Junya, additional, Carrot-Zhang, Jian, additional, McGranahan, Nicholas, additional, Ying, Lisha, additional, Fukuoka, Junya, additional, Chow, Chi-Wan, additional, Pham, Hoa, additional, Godoy, Myrna C.B., additional, Carter, Brett W., additional, Behrens, Carmen, additional, Zhang, Jianhua, additional, Antonoff, Mara B., additional, Sepesi, Boris, additional, Lu, Yue, additional, Pass, Harvey, additional, Kadara, Humam, additional, Scheet, Paul, additional, Vaporciyan, Ara A., additional, Heymach, John V., additional, Wistuba, Ignacio I., additional, Lee, J. Jack, additional, Futreal, P. Andrew, additional, Su, Dan, additional, Issa, Jean-Pierre J., additional, and Zhang, Jianjun, additional

Published
2020
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200. Intratumoural (IT) evolutionary landscape of high-risk prostate cancer and outcome: The PROGENY (PROstate cancer GENomic heterogeneitY) study of genomic and immune parameters.

Author

Jayaram, Anuradha, primary, Goh, Gerald, additional, Kularatne, Bihani Yoshana, additional, Waterhouse, Jasmin, additional, Shanmugabavan, Yaalini, additional, Rowan, Andrew, additional, Wong, Yien Ning Sophia, additional, Freeman, Alex, additional, Akarca, Ayse, additional, Herrero, Javier, additional, Rosenthal, Rachel, additional, McGranahan, Nicholas, additional, Hung, Michelle, additional, Emberton, Mark, additional, Attard, Gerhardt, additional, Quezada, Sergio A., additional, Marafioti, Teresa, additional, Ahmed, Hashim Uddin, additional, Swanton, Charles, additional, and Linch, Mark David, additional

Published
2020
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