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1. The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

Author

Caswell, Deborah R., Gui, Philippe, Mayekar, Manasi K., Law, Emily K., Pich, Oriol, Bailey, Chris, Boumelha, Jesse, Kerr, D. Lucas, Blakely, Collin M., Manabe, Tadashi, Martinez-Ruiz, Carlos, Bakker, Bjorn, De Dios Palomino Villcas, Juan, I. Vokes, Natalie, Dietzen, Michelle, Angelova, Mihaela, Gini, Beatrice, Tamaki, Whitney, Allegakoen, Paul, Wu, Wei, Humpton, Timothy J., Hill, William, Tomaschko, Mona, Lu, Wei-Ting, Haderk, Franziska, Al Bakir, Maise, Nagano, Ai, Gimeno-Valiente, Francisco, de Carné Trécesson, Sophie, Vendramin, Roberto, Barbè, Vittorio, Mugabo, Miriam, Weeden, Clare E., Rowan, Andrew, McCoach, Caroline E., Almeida, Bruna, Green, Mary, Gomez, Carlos, Nanjo, Shigeki, Barbosa, Dora, Moore, Chris, Przewrocka, Joanna, Black, James R. M., Grönroos, Eva, Suarez-Bonnet, Alejandro, Priestnall, Simon L., Zverev, Caroline, Lighterness, Scott, Cormack, James, Olivas, Victor, Cech, Lauren, Andrews, Trisha, Rule, Brandon, Jiao, Yuwei, Zhang, Xinzhu, Ashford, Paul, Durfee, Cameron, Venkatesan, Subramanian, Temiz, Nuri Alpay, Tan, Lisa, Larson, Lindsay K., Argyris, Prokopios P., Brown, William L., Yu, Elizabeth A., Rotow, Julia K., Guha, Udayan, Roper, Nitin, Yu, Johnny, Vogel, Rachel I., Thomas, Nicholas J., Marra, Antonio, Selenica, Pier, Yu, Helena, Bakhoum, Samuel F., Chew, Su Kit, Reis-Filho, Jorge S., Jamal-Hanjani, Mariam, Vousden, Karen H., McGranahan, Nicholas, Van Allen, Eliezer M., Kanu, Nnennaya, Harris, Reuben S., Downward, Julian, Bivona, Trever G., and Swanton, Charles

Abstract

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3Bexpression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3Bexpression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3Bexpression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3Bwas confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

Published
2024
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2. 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

Abstract

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

Published
2023
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3. 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

Abstract

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

Published
2023
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4. 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

Abstract

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.

Published
2023
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5. 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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6. 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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7. 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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8. 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, and Yuan, Yinyin

Abstract

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape1–5. 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
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9. 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., Zhou, Cong, Wilson, Gareth A., Jamal-Hanjani, Mariam, Birkbak, Nicolai, Pierce, Jackie, Kim, Chang Sik, Ferdous, Saba, Burt, Deborah J., Slane-Tan, Daniel, Gomes, Fabio, Moore, David, Shah, Rajesh, Al Bakir, Maise, Hiley, Crispin, Veeriah, Selvaraju, Summers, Yvonne, Crosbie, Philip, Ward, Sophia, Mesquita, Barbara, Dynowski, Marek, Biswas, Dhruva, Tugwood, Jonathan, Blackhall, Fiona, Miller, Crispin, Hackshaw, Allan, Brady, Ged, Swanton, Charles, and Dive, Caroline

Abstract

Approximately 50% of patients with early-stage non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent will relapse within 5 years1,2. Detection of circulating tumor cells (CTCs) at the time of surgery may represent a tool to identify patients at higher risk of recurrence for whom more frequent monitoring is advised. Here we asked whether CellSearch-detected pulmonary venous CTCs (PV-CTCs) at surgical resection of early-stage NSCLC represent subclones responsible for subsequent disease relapse. PV-CTCs were detected in 48% of 100 patients enrolled into the TRACERx study3, were associated with lung-cancer-specific relapse and remained an independent predictor of relapse in multivariate analysis adjusted for tumor stage. In a case study, genomic profiling of single PV-CTCs collected at surgery revealed higher mutation overlap with metastasis detected 10 months later (91%) than with the primary tumor (79%), suggesting that early-disseminating PV-CTCs were responsible for disease relapse. Together, PV-CTC enumeration and genomic profiling highlight the potential of PV-CTCs as early predictors of NSCLC recurrence after surgery. However, the limited sensitivity of PV-CTCs in predicting relapse suggests that further studies using a larger, independent cohort are warranted to confirm and better define the potential clinical utility of PV-CTCs in early-stage NSCLC.

Published
2019
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10. 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, Boeing, Stefan, Krzystanek, Marcin, Djureinovic, Dijana, La Fleur, Linnea, Greco, Maria, Döme, Balázs, Fillinger, János, Brunnström, Hans, Wu, Yin, Moore, David A., Skrzypski, Marcin, Abbosh, Christopher, Litchfield, Kevin, Al Bakir, Maise, Watkins, Thomas B. K., Veeriah, Selvaraju, Wilson, Gareth A., Jamal-Hanjani, Mariam, Moldvay, Judit, Botling, Johan, Chinnaiyan, Arul M., Micke, Patrick, Hackshaw, Allan, Bartek, Jiri, Csabai, Istvan, Szallasi, Zoltan, Herrero, Javier, McGranahan, Nicholas, and Swanton, Charles

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 stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2–6. 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.

Published
2019
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11. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Author

Abbosh, Christopher, Birkbak, Nicolai J., Wilson, Gareth A., Jamal-Hanjani, Mariam, Constantin, Tudor, Salari, Raheleh, Le Quesne, John, Moore, David A., Veeriah, Selvaraju, Rosenthal, Rachel, Marafioti, Teresa, Kirkizlar, Eser, Watkins, Thomas B. K., McGranahan, Nicholas, Ward, Sophia, Martinson, Luke, Riley, Joan, Fraioli, Francesco, Al Bakir, Maise, Grönroos, Eva, Zambrana, Francisco, Endozo, Raymondo, Bi, Wenya Linda, Fennessy, Fiona M., Sponer, Nicole, Johnson, Diana, Laycock, Joanne, Shafi, Seema, Czyzewska-Khan, Justyna, Rowan, Andrew, Chambers, Tim, Matthews, Nik, Turajlic, Samra, Hiley, Crispin, Lee, Siow Ming, Forster, Martin D., Ahmad, Tanya, Falzon, Mary, Borg, Elaine, Lawrence, David, Hayward, Martin, Kolvekar, Shyam, Panagiotopoulos, Nikolaos, Janes, Sam M., Thakrar, Ricky, Ahmed, Asia, Blackhall, Fiona, Summers, Yvonne, Hafez, Dina, Naik, Ashwini, Ganguly, Apratim, Kareht, Stephanie, Shah, Rajesh, Joseph, Leena, Marie Quinn, Anne, Crosbie, Phil A., Naidu, Babu, Middleton, Gary, Langman, Gerald, Trotter, Simon, Nicolson, Marianne, Remmen, Hardy, Kerr, Keith, Chetty, Mahendran, Gomersall, Lesley, Fennell, Dean A., Nakas, Apostolos, Rathinam, Sridhar, Anand, Girija, Khan, Sajid, Russell, Peter, Ezhil, Veni, Ismail, Babikir, Irvin-Sellers, Melanie, Prakash, Vineet, Lester, Jason F., Kornaszewska, Malgorzata, Attanoos, Richard, Adams, Haydn, Davies, Helen, Oukrif, Dahmane, Akarca, Ayse U., Hartley, John A., Lowe, Helen L., Lock, Sara, Iles, Natasha, Bell, Harriet, Ngai, Yenting, Elgar, Greg, Szallasi, Zoltan, Schwarz, Roland F., Herrero, Javier, Stewart, Aengus, Quezada, Sergio A., Peggs, Karl S., Van Loo, Peter, Dive, Caroline, Lin, C. Jimmy, Rabinowitz, Matthew, Aerts, Hugo J. W. L., Hackshaw, Allan, Shaw, Jacqui A., Zimmermann, Bernhard G., and Swanton, Charles

Abstract

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

Published
2017
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12. Publisher Correction: 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, Boeing, Stefan, Krzystanek, Marcin, Djureinovic, Dijana, La Fleur, Linnea, Greco, Maria, Döme, Balázs, Fillinger, János, Brunnström, Hans, Wu, Yin, Moore, David A., Skrzypski, Marcin, Abbosh, Christopher, Litchfield, Kevin, Al Bakir, Maise, Watkins, Thomas B. K., Veeriah, Selvaraju, Wilson, Gareth A., Jamal-Hanjani, Mariam, Moldvay, Judit, Botling, Johan, Chinnaiyan, Arul M., Micke, Patrick, Hackshaw, Allan, Bartek, Jiri, Csabai, Istvan, Szallasi, Zoltan, Herrero, Javier, McGranahan, Nicholas, and Swanton, Charles

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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13. 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., Zhou, Cong, Wilson, Gareth A., Jamal-Hanjani, Mariam, Birkbak, Nicolai, Pierce, Jackie, Kim, Chang Sik, Ferdous, Saba, Burt, Deborah J., Slane-Tan, Daniel, Gomes, Fabio, Moore, David, Shah, Rajesh, Al Bakir, Maise, Hiley, Crispin, Veeriah, Selvaraju, Summers, Yvonne, Crosbie, Philip, Ward, Sophia, Mesquita, Barbara, Dynowski, Marek, Biswas, Dhruva, Tugwood, Jonathan, Blackhall, Fiona, Miller, Crispin, Hackshaw, Allan, Brady, Ged, Swanton, Charles, and Dive, Caroline

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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14. Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue

Author

Litchfield, Kevin, Stanislaw, Stacey, Spain, Lavinia, Gallegos, Lisa L., Rowan, Andrew, Schnidrig, Desiree, Rosenbaum, Heidi, Harle, Alexandre, Au, Lewis, Hill, Samantha M., Tippu, Zayd, Thomas, Jennifer, Thompson, Lisa, Xu, Hang, Horswell, Stuart, Barhoumi, Aoune, Jones, Carol, Leith, Katherine F., Burgess, Daniel L., Watkins, Thomas B.K., Lim, Emilia, Birkbak, Nicolai J., Lamy, Philippe, Nordentoft, Iver, Dyrskjøt, Lars, Pickering, Lisa, Hazell, Stephen, Jamal-Hanjani, Mariam, Abbosh, Chris, Shiu, Kai-Keen, Bridgewater, John, Hochhauser, Daniel, Forster, Martin, Lee, Siow-Ming, Ahmad, Tanya, Papadatos-Pastos, Dionysis, Janes, Sam, Van Loo, Peter, Enfield, Katey, McGranahan, Nicholas, Huebner, Ariana, Quezada, Sergio, Beck, Stephan, Parker, Peter, Walczak, Henning, Enver, Tariq, Hynds, Rob, Falzon, Mary, Proctor, Ian, Sinclair, Ron, Lok, Chi-wah, Rhodes, Zoe, Moore, David, Marafioti, Teresa, Borg, Elaine, Mitchison, Miriam, Khiroya, Reena, Trevisan, Giorgia, Ellery, Peter, Linch, Mark, Brandner, Sebastian, Hiley, Crispin, Veeriah, Selvaraju, Razaq, Maryam, Shaw, Heather, Attard, Gert, Akther, Mita Afroza, Naceur-Lombardelli, Cristina, Manzano, Lizi, Al-Bakir, Maise, Summan, Simranpreet, Kanu, Nnenna, Ward, Sophie, Asghar, Uzma, Lim, Emilia, Gishen, Faye, Tookman, Adrian, Stone, Paddy, Stirling, Caroline, Furness, Andrew, Edmonds, Kim, Hunter, Nikki, Sarker, Sarah, Vaughan, Sarah, Mangwende, Mary, Pearce, Karla, Spain, Lavinia, Shepherd, Scott, Yan, Haixi, Shum, Ben, Carlyle, Eleanor, Hazell, Steve, Fendler, Annika, Byrne, Fiona, Yousaf, Nadia, Popat, Sanjay, Curtis, Olivia, Stamp, Gordon, Toncheva, Antonia, Nye, Emma, Murra, Aida, Korteweg, Justine, Sheikh, Nahid, Josephs, Debra, Chandra, Ashish, Spicer, James, Mahadeva, Ula, Green, Anna, Stewart, Ruby, Iredale, Lara-Rose, Mackay, Tina, Deakin, Ben, Enting, Debra, Rudman, Sarah, Ghosh, Sharmistha, Karapagniotou, Lena, Pintus, Elias, Tutt, Andrew, Howlett, Sarah, Michalarea, Vasiliki, Brenton, James, Caldas, Carlos, Fitzgerald, Rebecca, Jimenez-Linan, Merche, Provenzano, Elena, Cluroe, Alison, Stewart, Grant, Watts, Colin, Gilbertson, Richard, McDermott, Ultan, Tavare, Simon, Beddowes, Emma, Roxburgh, Patricia, Biankin, Andrew, Chalmers, Anthony, Fraser, Sioban, Oien, Karin, Kidd, Andrew, Blyth, Kevin, Krebs, Matt, Blackhall, Fiona, Summers, Yvonne, Dive, Caroline, Marais, Richard, Gomes, Fabio, Carter, Mat, Dransfield, Jo, Le Quesne, John, Fennell, Dean, Shaw, Jacqui, Naidu, Babu, Baijal, Shobhit, Tanchel, Bruce, Langman, Gerald, Robinson, Andrew, Collard, Martin, Cockcroft, Peter, Ferris, Charlotte, Bancroft, Hollie, Kerr, Amy, Middleton, Gary, Webb, Joanne, Kadiri, Salma, Colloby, Peter, Olisemeke, Bernard, Wilson, Rodelaine, Tomlinson, Ian, Jogai, Sanjay, Ottensmeier, Christian, Harrison, David, Loda, Massimo, Flanagan, Adrienne, McKenzie, Mairead, Hackshaw, Allan, Ledermann, Jonathan, Sharp, Abby, Farrelly, Laura, Bridger, Hayley, Larkin, James, Swanton, Charles, Alexander, Nelson R., and Turajlic, Samra

Abstract

Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

Published
2020
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15. Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Author

Abbosh, Christopher, Birkbak, Nicolai J., Wilson, Gareth A., Jamal-Hanjani, Mariam, Constantin, Tudor, Salari, Raheleh, Le Quesne, John, Moore, David A., Veeriah, Selvaraju, Rosenthal, Rachel, Marafioti, Teresa, Kirkizlar, Eser, Watkins, Thomas B. K., McGranahan, Nicholas, Ward, Sophia, Martinson, Luke, Riley, Joan, Fraioli, Francesco, Al Bakir, Maise, Grönroos, Eva, Zambrana, Francisco, Endozo, Raymondo, Bi, Wenya Linda, Fennessy, Fiona M., Sponer, Nicole, Johnson, Diana, Laycock, Joanne, Shafi, Seema, Czyzewska-Khan, Justyna, Rowan, Andrew, Chambers, Tim, Matthews, Nik, Turajlic, Samra, Hiley, Crispin, Lee, Siow Ming, Forster, Martin D., Ahmad, Tanya, Falzon, Mary, Borg, Elaine, Lawrence, David, Hayward, Martin, Kolvekar, Shyam, Panagiotopoulos, Nikolaos, Janes, Sam M., Thakrar, Ricky, Ahmed, Asia, Blackhall, Fiona, Summers, Yvonne, Hafez, Dina, Naik, Ashwini, Ganguly, Apratim, Kareht, Stephanie, Shah, Rajesh, Joseph, Leena, Quinn, Anne Marie, Crosbie, Phil A., Naidu, Babu, Middleton, Gary, Langman, Gerald, Trotter, Simon, Nicolson, Marianne, Remmen, Hardy, Kerr, Keith, Chetty, Mahendran, Gomersall, Lesley, Fennell, Dean A., Nakas, Apostolos, Rathinam, Sridhar, Anand, Girija, Khan, Sajid, Russell, Peter, Ezhil, Veni, Ismail, Babikir, Irvin-Sellers, Melanie, Prakash, Vineet, Lester, Jason F., Kornaszewska, Malgorzata, Attanoos, Richard, Adams, Haydn, Davies, Helen, Oukrif, Dahmane, Akarca, Ayse U., Hartley, John A., Lowe, Helen L., Lock, Sara, Iles, Natasha, Bell, Harriet, Ngai, Yenting, Elgar, Greg, Szallasi, Zoltan, Schwarz, Roland F., Herrero, Javier, Stewart, Aengus, Quezada, Sergio A., Peggs, Karl S., Van Loo, Peter, Dive, Caroline, Lin, C. Jimmy, Rabinowitz, Matthew, Aerts, Hugo J. W. L., Hackshaw, Allan, Shaw, Jacqui A., Zimmermann, Bernhard G., and Swanton, Charles

Abstract

This corrects the article DOI: 10.1038/nature22364

Published
2018
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