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1. Genomic-transcriptomic evolution in lung cancer and metastasis

Author

Martínez-Ruiz, Carlos, Black, James RM, Puttick, Clare, Hill, Mark S, Demeulemeester, Jonas, Cadieux, Elizabeth Larose, 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 BK, 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, Consortium, TRACERx, Swanton, Charles, and McGranahan, Nicholas

Subjects
Model organisms, Chemical Biology & High Throughput, Human Biology & Physiology, Stem Cells, FOS: Clinical medicine, Genome Integrity & Repair, Immunology, Gene Expression, Cell Biology, Tumour Biology, Signalling & Oncogenes, Ecology,Evolution & Ethology, Cell Cycle & Chromosomes, Genetics & Genomics, Computational & Systems Biology
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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2. USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development

Author

Novellasdemunt, Laura, Kucharska, Anna, Baulies, Anna, Hutton, Colin, Vlachogiannis, Georgios, Repana, Dimitra, Rowan, Andrew, Suárez-Bonnet, A, Ciccarelli, Francesca, Valeri, Nicola, and Li, Vivian SW

Subjects
Human Biology & Physiology, Signalling & Oncogenes, Stem Cells, Tumour Biology, Developmental Biology
Abstract

Adenomatous polyposis coli (APC) mutation is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its on-target toxicity. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing β-catenin, but its role in gut tumorigenesis is unknown. Here, we show in vivo that deletion of Usp7 in Apc-truncated mice inhibits crypt hyperproliferation and intestinal tumor development. Loss of Usp7 prolongs the survival of the sporadic intestinal tumor model. Genetic deletion, but not pharmacological inhibition, of Usp7 in Apc+/- intestine induces colitis and enteritis. USP7 inhibitor treatment suppresses growth of patient-derived cancer organoids carrying APC truncations in vitro and in xenografts. Our findings provide direct evidence that USP7 inhibition may offer a safe and efficacious tumor-specific therapy for both sporadic and germline APC-mutated CRC.

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

Author

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

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

Understanding the evolutionary pathways to metastasis and resistance to immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present the most comprehensive intra-patient metastatic melanoma dataset assembled to date as part of the PEACE research autopsy programme, including 222 exome, 493 panel-sequenced, 161 RNA-seq, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI non-responders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one of the patients. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.

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

Author

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

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

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

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

Author

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

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

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

Published
2022
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6. Compression of Fatigue Spectra for Composite Materials

Author

HEALEY, ROWAN ANDREW

Subjects
Mechanical Engineering, FOS: Mechanical engineering
Abstract

In this study a ground up approach was taken to develop a loading sequence simplification methodology for use with composite specimens undergoing mode II delamination. Models developed from fatigue data informed the application of two techniques: truncation and cycle merging. Experimental results showed good agreement with predictions for the truncated sequences which achieved length reductions of 77% and 74% for unidirectional and woven specimens respectively. By first performing truncation, cycle merging was successfully implemented achieving a 95% length reduction. The application of scaling allowed for damage to be re-introduced/removed, enabling the damage content to be matched with the original sequence.

Published
2022
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7. Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study

Author

Fu, Xiao, Zhao, Yue, Lopez, Jose I, Rowan, Andrew, Au, Lewis, Fendler, Annika, Hazell, Steve, Xu, Hang, Horswell, Stuart, Shepherd, Scott TC, Spencer, Charlotte E, Spain, Lavinia, Byrne, Fiona, Stamp, Gordon, O'Brien, Tim, Nicol, David, Augustine, Marcellus, Chandra, Ashish, Rudman, Sarah, Toncheva, Antonia, Furness, Andrew JS, Pickering, Lisa, Kumar, Santosh, Koh, Dow-Mu, Messiou, Christina, Dafydd, Derfel ap, Orton, Matthew R, Doran, Simon J, Larkin, James, Swanton, Charles, Sahai, Erik, Litchfield, Kevin, Turajlic, Samra, Consortium, TRACERx Renal, and Bates, Paul A

Subjects
Model organisms, Chemical Biology & High Throughput, Signalling & Oncogenes, Human Biology & Physiology, Ecology,Evolution & Ethology, Genome Integrity & Repair, Cell Biology, Tumour Biology, Genetics & Genomics, Imaging, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution.

Published
2022
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8. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Author

Au, Lewis, Hatipoglu, Emine, Robert De Massy, Marc, Litchfield, Kevin, Beattie, Gordon, Rowan, Andrew, Schnidrig, Desiree, Thompson, Rachael, Byrne, Fiona, Horswell, Stuart, Fotiadis, Nicos, Hazell, Steve, Nicol, David, Shepherd, Scott TC, Fendler, Annika, Mason, Robert, Del Rosario, Lyra, Edmonds, Kim, Lingard, Karla, Sarker, Sarah, Mangwende, Mary, Carlyle, Eleanor, Attig, Jan, Joshi, Kroopa, Uddin, Imran, Becker, Pablo D, Sunderland, Mariana Werner, Akarca, Ayse, Puccio, Ignazio, Yang, William W, Lund, Tom, Dhillon, Kim, Vasquez, Marcos Duran, Ghorani, Ehsan, Xu, Hang, Spencer, Charlotte, López, José I, Green, Anna, Mahadeva, Ula, Borg, Elaine, Mitchison, Miriam, Moore, David A, Proctor, Ian, Falzon, Mary, Pickering, Lisa, Furness, Andrew JS, Reading, James L, Salgado, Roberto, Marafioti, Teresa, Jamal-Hanjani, Mariam, PEACE Consortium, Kassiotis, George, Chain, Benny, Larkin, James, Swanton, Charles, Quezada, Sergio A, Turajlic, Samra, TRACERx Renal Consortium, and Apollo - University of Cambridge Repository

Subjects
multiregion, Receptors, Antigen, T-Cell, clear cell renal cell carcinoma, CD8-Positive T-Lymphocytes, autopsy, Clinical Trials, Phase II as Topic, Exome Sequencing, Tumor Microenvironment, Humans, TCR clonal replacement, Prospective Studies, TCR clonal maintenance, Carcinoma, Renal Cell, Immune Checkpoint Inhibitors, nivolumab, Sequence Analysis, RNA, Gene Expression Profiling, Endogenous Retroviruses, Genomics, Kidney Neoplasms, human endogenous retrovirus, Drug Resistance, Neoplasm, anti-PD-1, Tumor Escape, T cell receptor, Single-Cell Analysis
Abstract

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Published
2021

9. Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Author

Turajlic, Samra, Xu, Hang, Litchfield, Kevin, Rowan, Andrew, Horswell, Stuart, Chambers, Tim, O'Brien, Tim, Lopez, Jose I, Watkins, Thomas BK, Nicol, David, Stares, Mark, Challacombe, Ben, Hazell, Steve, Chandra, Ashish, Mitchell, Thomas J, Au, Lewis, Eichler-Jonsson, Claudia, Jabbar, Faiz, Soultati, Aspasia, Chowdhury, Simon, Rudman, Sarah, Lynch, Joanna, Fernando, Archana, Stamp, Gordon, Nye, Emma, Stewart, Aengus, Xing, Wei, Smith, Jonathan C, Escudero, Mickael, Huffman, Adam, Matthews, Nik, Elgar, Greg, Phillimore, Ben, Costa, Marta, Begum, Sharmin, Ward, Sophia, Salm, Max, Boeing, Stefan, Fisher, Rosalie, Spain, Lavinia, Navas, Carolina, Grönroos, Eva, Hobor, Sebastijan, Sharma, Sarkhara, Aurangzeb, Ismaeel, Lall, Sharanpreet, Polson, Alexander, Varia, Mary, Horsfield, Catherine, Fotiadis, Nicos, Pickering, Lisa, Schwarz, Roland F, Silva, Bruno, Herrero, Javier, Luscombe, Nick M, Jamal-Hanjani, Mariam, Rosenthal, Rachel, Birkbak, Nicolai J, Wilson, Gareth A, Pipek, Orsolya, Ribli, Dezso, Krzystanek, Marcin, Csabai, Istvan, Szallasi, Zoltan, Gore, Martin, McGranahan, Nicholas, Van Loo, Peter, Campbell, Peter, Larkin, James, Swanton, Charles, TRACERx Renal Consortium, Mitchell, Thomas [0000-0003-0761-9503], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, intratumor heterogeneity, branched evolution, linear evolution, renal cell cancer, Chromosomes, Clonal Evolution, Evolution, Molecular, Genetic Heterogeneity, deterministic evolution, Biomarkers, Tumor, metastasis, Humans, Longitudinal Studies, Prospective Studies, Neoplasm Metastasis, Carcinoma, Renal Cell, Alleles, Phylogeny, Aged, Aged, 80 and over, cancer evolution, Models, Statistical, tumor diversity, Genetic Variation, punctuated evolution, Sequence Analysis, DNA, Middle Aged, Prognosis, Kidney Neoplasms, Phenotype, Mutation, Disease Progression, Female, chromosome instability
Abstract

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Published
2018
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10. Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

Author

Mitchell, Thomas J, Turajlic, Samra, Rowan, Andrew, Nicol, David, Farmery, James HR, O'Brien, Tim, Martincorena, Inigo, Tarpey, Patrick, Angelopoulos, Nicos, Yates, Lucy R, Butler, Adam P, Raine, Keiran, Stewart, Grant D, Challacombe, Ben, Fernando, Archana, Lopez, Jose I, Hazell, Steve, Chandra, Ashish, Chowdhury, Simon, Rudman, Sarah, Soultati, Aspasia, Stamp, Gordon, Fotiadis, Nicos, Pickering, Lisa, Au, Lewis, Spain, Lavinia, Lynch, Joanna, Stares, Mark, Teague, Jon, Maura, Francesco, Wedge, David C, Horswell, Stuart, Chambers, Tim, Litchfield, Kevin, Xu, Hang, Stewart, Aengus, Elaidi, Reza, Oudard, Stéphane, McGranahan, Nicholas, Csabai, Istvan, Gore, Martin, Futreal, P Andrew, Larkin, James, Lynch, Andy G, Szallasi, Zoltan, Swanton, Charles, Campbell, Peter J, TRACERx Renal Consortium, Mitchell, Thomas [0000-0003-0761-9503], Stewart, Grant [0000-0003-3188-9140], Lynch, Andy [0000-0002-7876-7338], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, cancer evolution, Genome, Human, Gene Dosage, clear cell renal cell carcinoma, Middle Aged, Kidney Neoplasms, Von Hippel-Lindau Tumor Suppressor Protein, Mutation, Disease Progression, chromothripsis, Chromosomes, Human, Pair 5, Humans, Female, Chromosomes, Human, Pair 3, Prospective Studies, 5' Untranslated Regions, Carcinoma, Renal Cell, Telomerase, Aged
Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Published
2018
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11. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal

Author

Turajlic, Samra, Xu, Hang, Litchfield, Kevin, Rowan, Andrew, Chambers, Tim, Lopez, Jose I, Nicol, David, O'Brien, Tim, Larkin, James, Horswell, Stuart, Stares, Mark, Au, Lewis, Jamal-Hanjani, Mariam, Challacombe, Ben, Chandra, Ashish, Hazell, Steve, Eichler-Jonsson, Claudia, Soultati, Aspasia, Chowdhury, Simon, Rudman, Sarah, Lynch, Joanna, Fernando, Archana, Stamp, Gordon, Nye, Emma, Jabbar, Faiz, Spain, Lavinia, Lall, Sharanpreet, Guarch, Rosa, Falzon, Mary, Proctor, Ian, Pickering, Lisa, Gore, Martin, Watkins, Thomas BK, Ward, Sophia, Stewart, Aengus, DiNatale, Renzo, Becerra, Maria F, Reznik, Ed, Hsieh, James J, Richmond, Todd A, Mayhew, George F, Hill, Samantha M, McNally, Catherine D, Jones, Carol, Rosenbaum, Heidi, Stanislaw, Stacey, Burgess, Daniel L, Alexander, Nelson R, Swanton, Charles, PEACE, TRACERx Renal Consortium, Turajlic, Samra [0000-0001-8846-136X], Litchfield, Kevin [0000-0002-3725-0914], Lopez, Jose I [0000-0003-0842-5348], Horswell, Stuart [0000-0003-2787-1933], Spain, Lavinia [0000-0002-9356-8812], Stewart, Aengus [0000-0001-5182-653X], DiNatale, Renzo [0000-0002-7867-2881], Mayhew, George F [0000-0003-0609-6018], Swanton, Charles [0000-0002-4299-3018], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, evolution of metastasis, Biopsy, renal cell cancer, loss of 9p, solitary metastasis, metastasis, Humans, Longitudinal Studies, Prospective Studies, Neoplasm Metastasis, Carcinoma, Renal Cell, Aged, Aged, 80 and over, Chromosomes, Human, Pair 14, Chromosome Mapping, Thrombosis, Middle Aged, Kidney Neoplasms, oligometastasis, Phenotype, Treatment Outcome, Mutation, Disease Progression, Female, chromosome instability, metastasectomy, Chromosomes, Human, Pair 9, Biomarkers, cytoreductive nephrectomy
Abstract

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

Published
2018

12. Matriptase Induction of Metalloproteinase-Dependent Aggrecanolysis In Vitro and In Vivo: Promotion of Osteoarthritic Cartilage Damage by Multiple Mechanisms

Author

Wilkinson, David J, Wang, Hui, Habgood, Angela, Lamb, Heather K, Thompson, Paul, Hawkins, Alastair R, Désilets, Antoine, Leduc, Richard, Steinmetzer, Torsten, Hammami, Maya, Lee, Melody S, Craik, Charles S, Watson, Sharon, Lin, Hua, Milner, Jennifer M, and Rowan, Andrew D

Subjects
Male, and over, In Vitro Techniques, Real-Time Polymerase Chain Reaction, Antibodies, Mice, Osteoarthritis, Endopeptidases, 80 and over, Animals, Humans, Knee, Aggrecans, Neutralizing, Aged, Blotting, Gene Expression Profiling, Serine Endopeptidases, Membrane Proteins, Middle Aged, musculoskeletal system, Immunohistochemistry, Matrix Metalloproteinases, Recombinant Proteins, Cartilage, Tibial, Menisci, ADAMTS4 Protein, Female, ADAMTS5 Protein, Western, Low Density Lipoprotein Receptor-Related Protein-1, Articular
Abstract

ObjectiveTo assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA.MethodsAggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction. Murine OA was induced by surgical destabilization of the medial meniscus, and matriptase inhibitors were administered via osmotic minipump or intraarticular injection. Cartilage damage was scored histologically and aggrecan cleavage was visualized immunohistochemically using specific neoepitope antibodies.ResultsThe addition of soluble recombinant matriptase promoted a time-dependent release of aggrecan (and collagen) from OA cartilage, which was sensitive to metalloproteinase inhibition and protease-activated receptor 2 antagonism. Although engineered human (normal) cartilage discs failed to release aggrecan following matriptase addition, both matrix metalloproteinase- and aggrecanase-mediated cleavages of aggrecan were detected in human OA cartilage. Additionally, while matriptase did not directly degrade aggrecan, it promoted the accumulation of low-density lipoprotein receptor-related protein 1 (LRP-1) in conditioned media of the OA cartilage explants. Matriptase inhibition via neutralizing antibody or small molecule inhibitor significantly reduced cartilage damage scores in murine OA, which was associated with reduced generation of metalloproteinase-mediated aggrecan cleavage.ConclusionMatriptase potently induces the release of metalloproteinase-generated aggrecan fragments as well as soluble LRP-1 from OA cartilage. Therapeutic targeting of matriptase proteolytic activity reduces metalloproteinase activity, further suggesting that this serine proteinase may have potential as a disease-modifying therapy in OA.

Published
2017

13. Oral Abstracts 7: RA Clinical * O37. Long-Term Outcomes of Early RA Patients Initiated with Adalimumab Plus Methotrexate Compared with Methotrexate Alone Following a Targeted Treatment Approach

Author

Fleischmann, Roy, van Vollenhoven, Ronald F., Smolen, Josef, Emery, Paul, Florentinus, Stefan, Rathmann, Suchitrita, Kupper, Hartmut, Kavanaugh, Arthur, Taylor, Peter, Genovese, Mark, Keystone, Edward C., Drescher, Edit, Berclaz, Pierre-Yves, Lee, Chin, Fidelus-Gort, Rosalind, Schlichting, Douglas, Beattie, Scott, Luchi, Monica, Macias, William, Dikranian, Ara H., Alten, Rieke, Klearman, Micki, Musselman, David, Agarwal, Sunil, Green, Jennifer, Gabay, Cem, Weinblatt, Michael E., Schiff, Michael H., Valente, Robert, van der Heijde, Desiree, Citera, Gustavo, Zhao, Cathy, Maldonado, Michael A., Rakieh, Chadi, Nam, Jacqueline L., Hunt, Laura, Villeneuve, Edith, Bissell, Lesley-Anne, Das, Sudipto, Conaghan, Philip, McGonagle, Dennis, Wakefield, Richard J., Wright, Helen L., Thomas, Huw B., Moots, Robert, Edwards, Steven W., Hamann, Philip, Heward, James, McHugh, Neil, Lindsay, Mark A., Haroon, Muhammad, Giles, Jon T., Winchester, Robert, FitzGerald, Oliver, Karaderi, Tugce, Cohen, Carla J., Keidel, Sarah, Appleton, Louise H., Macfarlane, Gary J., Siebert, Stefan, Evans, David, Paul Wordsworth, B., Plant, Darren, Bowes, John, Orozco, Gisela, Morgan, Ann W., Wilson, Anthony G., Isaacs, John, Barton, Anne, Williams, Frances M., Livshits, Gregory, Spector, Tim, MacGregor, Alexander, Scollen, Serena, Cao, Dandan, Memari, Yasin, Hyde, Craig L., Zhang, Baohong, Sidders, Benjamin, Ziemek, Daniel, Shi, Yujian, Harris, Juliette, Harrow, Ian, Dougherty, Brian, Malarstig, Anders, McEwen, Robert, Stephens, Joel L., Patel, Ketan, Shin, So-Youn, Surdulescu, Gabriela, He, Wen, Jin, Xin, McMahon, Stephen B., Soranzo, Nicole, John, Sally, Wang, Jun, Spector, Tim D., Baker, Jonathan, Litherland, Gary J., Rowan, Andrew D., Kite, Kerry A., Bayley, Rachel, Yang, Peiming, Smith, Jacqueline P., Williams, Julie, Harper, Lorraine, Kitas, George D., Buckley, Christopher, Young, Stephen P., Fitzpatrick, Martin A., McGettrick, Helen M., Filer, Andrew, Raza, Karim, Nash, Gerard, Muthana, Munitta, Davies, Holly, Khetan, Sachin, Adeleke, Gbadebo, Hawtree, Sarah, Tazzyman, Simon, Morrow, Fiona, Ciani, Barbara, Wilson, Gerry, Quirke, Anne-Marie, Lugli, Elena, Wegner, Natalia, Charles, Peter, Hamilton, Bart, Chowdhury, Muslima, Ytterberg, Jimmy, Potempa, Jan, Fisher, Benjamin, Thiele, Geoffrey, Mikuls, Ted, Venables, Patrick, Adebajo, Adewale O., Mease, Philip, Gomez-Reino, Juan J., Wollenhaupt, Jurgen, Hu, ChiaChi, Stevens, Randall, Sieper, Joachim, Dougados, Maxime, Van den Bosch, Filip, Goupille, Philippe, Rathmann, Suchitrita S., Pangan, Aileen L., Maksymowych, Walter P., Brown, Matthew A., Elewaut, Dirk, Anderson, Jaclyn, Ramasamy, Pathma, O'Rourke, Michael, Murphy, Conor, Fitzgerald, Oliver, Jani, Meghna, Moore, Sarah, Mirjafari, Hoda, Macphie, Elizabeth, Chinoy, Hector, Rao, Chan, McLoughlin, Yokemei, and Preeti, Shah

Subjects
medicine.medical_specialty, Rheumatology, business.industry, Radiography, medicine, Pharmacology (medical), Inflammation, In patient, Radiology, medicine.symptom, Axial spondyloarthritis, business, Joint (geology)
Abstract

Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (

Published
2013

14. Common non-synonymous snps associated with breast cancer susceptibility: findings from the breast cancer association consortium

Author

Milne, Roger L., Burwinkel, Barbara, Michailidou, Kyriaki, Arias-Perez, Jose-Ignacio, Zamora, M. Pilar, Menéndez-Rodríguez, Primitiva, Hardisson, David, Mendiola, Marta, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Dennis, Joe, Wang, Qin, Bolla, Manjeet K., Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Schoemaker, Minouk, Ko, Yon-Dschun, Brauch, Hiltrud, Hamann, Ute, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tajima, Kazuo, Li, Jingmei, Brand, Judith S., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Lambrechts, Diether, Peuteman, Gilian, Christiaens, Marie-Rose, Smeets, Ann, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katazyna, Hartman, Mikael, Hui, Miao, Yen Lim, Wei, Wan Chan, Ching, Marme, Federick, Yang, Rongxi, Bugert, Peter, Lindblom, Annika, Margolin, Sara, García-Closas, Montserrat, Chanock, Stephen J., Lissowska, Jolanta, Figueroa, Jonine D., Bojesen, Stig E., Nordestgaard, Børge G., Flyger, Henrik, Hooning, Maartje J., Kriege, Mieke, van den Ouweland, Ans M.W., Koppert, Linetta B., Fletcher, Olivia, Johnson, Nichola, dos-Santos-Silva, Isabel, Peto, Julian, Zheng, Wei, Deming-Halverson, Sandra, Shrubsole, Martha J., Long, Jirong, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Cox, Angela, Cross, Simon S., Reed, Malcolm W.R., Schmidt, Marjanka K., Broeks, Annegien, Cornelissen, Sten, Braaf, Linde, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K., Noh, Dong-Young, Simard, Jacques, Dumont, Martine, Goldberg, Mark S., Labrèche, France, Fasching, Peter A., Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Radice, Paolo, Peterlongo, Paolo, Azzollini, Jacopo, Barile, Monica, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Hopper, John L., Schmidt, Daniel F., Makalic, Enes, Southey, Melissa C., Hwang Teo, Soo, Har Yip, Cheng, Sivanandan, Kavitta, Tay, Wan-Ting, Shen, Chen-Yang, Hsiung, Chia-Ni, Yu, Jyh-Cherng, Hou, Ming-Feng, Guénel, Pascal, Truong, Therese, Sanchez, Marie, Mulot, Claire, Blot, William, Cai, Qiuyin, Nevanlinna, Heli, Muranen, Taru A., Aittomäki, Kristiina, Blomqvist, Carl, Wu, Anna H., Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O., Bogdanova, Natalia, Dörk, Thilo, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Zhang, Ben, Couch, Fergus J., Toland, Amanda E., Yannoukakos, Drakoulis, Sangrajrang, Suleeporn, McKay, James, Wang, Xianshu, Olson, Janet E., Vachon, Celine, Purrington, Kristen, Severi, Gianluca, Baglietto, Laura, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Devilee, Peter, Tollenaar, Robert A.E.M., Seynaeve, Caroline, Czene, Kamila, Eriksson, Mikael, Humphreys, Keith, Darabi, Hatef, Ahmed, Shahana, Shah, Mitul, Pharoah, Paul D.P., Hall, Per, Giles, Graham G., Benítez, Javier, Dunning, Alison M., Chenevix-Trench, Georgia, Easton, Douglas F., Berchuck, Andrew, Eeles, Rosalind A., Olama, Ali Amin Al, Kote-Jarai, Zsofia, Benlloch, Sara, Antoniou, Antonis, McGuffog, Lesley, Offit, Ken, Lee, Andrew, Dicks, Ed, Luccarini, Craig, Tessier, Daniel C., Bacot, Francois, Vincent, Daniel, LaBoissière, Sylvie, Robidoux, Frederic, Nielsen, Sune F., Cunningham, Julie M., Windebank, Sharon A., Hilker, Christopher A., Meyer, Jeffrey, Angelakos, Maggie, Maskiell, Judi, van der Schoot, Ellen, Rutgers, Emiel, Verhoef, Senno, Hogervorst, Frans, Boonyawongviroj, Prat, Siriwanarungsan, Pornthep, Schrauder, Michael, Rübner, Matthias, Oeser, Sonja, Landrith, Silke, Williams, Eileen, Ryder-Mills, Elaine, Sargus, Kara, McInerney, Niall, Colleran, Gabrielle, Rowan, Andrew, Jones, Angela, Sohn, Christof, Schneeweiß, Andeas, Álvarez, Núria, Lacey, James, Wang, Sophia, Ma, Huiyan, Lu, Yani, Deapen, Dennis, Pinder, Rich, Lee, Eunjung, Schumacher, Fred, Horn-Ross, Pam, Reynolds, Peggy, Nelson, David, Ziegler, Hartwig, Wolf, Sonja, Hermann, Volker, Lo, Wing-Yee, Justenhoven, Christina, Baisch, Christian, Fischer, Hans-Peter, Brüning, Thomas, Pesch, Beate, Rabstein, Sylvia, Lotz, Anne, Harth, Volker, Heikkinen, Tuomas, Erkkilä, Irja, Aaltonen, Kirsimari, von Smitten, Karl, Antonenkova, Natalia, Hillemanns, Peter, Christiansen, Hans, Myöhänen, Eija, Kemiläinen, Helena, Thorne, Heather, Niedermayr, Eveline, Bowtell, D, Chenevix-Trench, G, deFazio, A, Gertig, D, Green, A, Webb, P, Green, A., Parsons, P., Hayward, N., Webb, P., Whiteman, D., Fung, Annie, Yashiki, June, Smeets, Dominiek, Brussel, Thomas Van, Corthouts, Kathleen, Obi, Nadia, Heinz, Judith, Behrens, Sabine, Eilber, Ursula, Celik, Muhabbet, Olchers, Til, Manoukian, Siranoush, Peissel, Bernard, Scuvera, Giulietta, Zaffaroni, Daniela, Bonanni, Bernardo, Feroce, Irene, Maniscalco, Angela, Rossi, Alessandra, Bernard, Loris, Tranchant, Martine, Valois, Marie-France, Turgeon, Annie, Heguy, Lea, Sze Yee, Phuah, Kang, Peter, Nee, Kang In, Mariapun, Shivaani, Sook-Yee, Yoon, Lee, Daphne, Ching, Teh Yew, Taib, Nur Aishah Mohd, Otsukka, Meeri, Mononen, Kari, Selander, Teresa, Weerasooriya, Nayana, staff, OFBCR, Krol-Warmerdam, E., Molenaar, J., Blom, J., Brinton, Louise, Szeszenia-Dabrowska, Neonila, Peplonska, Beata, Zatonski, Witold, Chao, Pei, Stagner, Michael, Bos, Petra, Blom, Jannet, Crepin, Ellen, Nieuwlaat, Anja, Heemskerk, Annette, Higham, Sue, Cross, Simon, Cramp, Helen, Connley, Dan, Balasubramanian, Sabapathy, Brock, Ian, Conroy, Don, Baynes, Caroline, and Chua, Kimberley

Subjects
Adult, A Kinase Anchor Proteins, Alleles, Ataxin-7, Breast Neoplasms, Case-Control Studies, Cytoskeletal Proteins, Female, Genome-Wide Association Study, Humans, Middle Aged, Nerve Tissue Proteins, Protein-Serine-Threonine Kinases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Molecular Biology, Genetics, Genetics (clinical), Protein Serine-Threonine Kinases, Medizinische Fakultät, NIMA-Related Kinases, ddc:610, Polymorphism, risk, variants, Association Studies Articles, identifies 2, Single Nucleotide, confer susceptibility, 5p12, loci, alleles, genome-wide association, metaanalysis
Abstract

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Published
2014

15. Directed evolution study of temperature adaptation in a psychrophilic enzyme 1 1Edited by J. A. Wells

Author

Donn Nelton Rubingh, Kentaro Miyazaki, Rowan Andrew Grayling, Frances H. Arnold, and Patrick L. Wintrode

Subjects
Biochemistry, Structural Biology, Thermophile, Biophysics, Subtilisin, Biology, Saturated mutagenesis, Psychrophile, Directed evolution, Molecular Biology, In vitro recombination, Thermostability, DNA shuffling
Abstract

We have used laboratory evolution methods to enhance the thermostability and activity of the psychrophilic protease subtilisin S41, with the goal of investigating the mechanisms by which this enzyme can adapt to different selection pressures. A combined strategy of random mutagenesis, saturation mutagenesis and in vitro recombination (DNA shuffling) was used to generate mutant libraries, which were screened to identify enzymes that acquired greater thermostability without sacrificing low-temperature activity. The half-life of seven-amino acid substitution variant 3-2G7 at 60 degrees C is approximately 500 times that of wild-type and far surpasses those of homologous mesophilic subtilisins. The dependence of half-life on calcium concentration indicates that enhanced calcium binding is largely responsible for the increased stability. The temperature optimum of the activity of 3-2G7 is shifted upward by approximately 10 degrees C. Unlike natural thermophilic enzymes, however, the activity of 3-2G7 at low temperatures was not compromised. The catalytic efficiency, k(cat)/K(M), was enhanced approximately threefold over a wide temperature range (10 to 60 degrees C). The activation energy for catalysis, determined by the temperature dependence of k(cat)/K(M) in the range 15 to 35 degrees C, is nearly identical to wild-type and close to half that of its highly similar mesophilic homolog, subtilisin SSII, indicating that the evolved S41 enzyme retained its psychrophilic character in spite of its dramatically increased thermostability. These results demonstrate that it is possible to increase activity at low temperatures and stability at high temperatures simultaneously. The fact that enzymes displaying both properties are not found in nature most likely reflects the effects of evolution, rather than any intrinsic physical-chemical limitations on proteins.

Published
2000

16. Correspondence

Author

Bhagwati, Jagdish N., Horowitz, Irving Louis, Howland, Jacob, Kohler, Judy, Rowan, Andrew N., Lussenhop, Tom, Whlean, Ken, Weiskopf, Doug, DeLapa, Michael, Weinstein, James, and Suarez, John Peter

Subjects
Economics
Abstract

Presents letters to the editor referencing articles and topics discussed in previous issues. "The Power of Pets," which discussed the passion of U.S. citizen for pets; "Not Two Cents," which focused on foreign policy writings by Thomas Friedman; "Kinder Cuts," which suggested the need for the U.S. administration to focus on balancing the budget and practicing fiscal responsibility.

Published
1995
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18. 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

Subjects
Lung Neoplasms, APOBEC-1 Deaminase, Smoking, Gene Dosage, Prognosis, Genomic Instability, Translocation, Genetic, respiratory tract diseases, 3. Good health, Evolution, Molecular, Genetic Heterogeneity, Carcinoma, Non-Small-Cell Lung, Cytidine Deaminase, Mutation, Carcinogens, Tumor Cells, Cultured, Humans, Neoplasm Recurrence, Local
Abstract

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

19. Effect of suppression of arabinoxylan synthetic genes in wheat endosperm on chain length of arabinoxylan and extract viscosity

Author

Alison Lovegrove, Luc Saulnier, Mark Wilkinson, Rowan A. C. Mitchell, Peter R. Shewry, Jackie Freeman, Rothamsted Research, Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Designing Seeds' Institute Strategic Programme from the Biotechnology and Biosciences Research Council of the United Kingdom, and Mitchell, Rowan Andrew Craig

Subjects
0106 biological sciences, 0301 basic medicine, Arabinose, Intrinsic viscosity, Flour, Plant Science, Biology, Alkalies, Polysaccharide, Genes, Plant, 01 natural sciences, Endosperm, Cell wall, wheat flour-processing properties, 03 medical and health sciences, chemistry.chemical_compound, Viscosity, grass xylan, Type II cell wall, RNA interference, Botany, Arabinoxylan, [SDV.IDA]Life Sciences [q-bio]/Food engineering, [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, Triticum, Research Articles, 2. Zero hunger, chemistry.chemical_classification, wheat flour‐processing properties, Plant Extracts, Plant Sciences, Homozygote, food and beverages, Water, Biosynthetic Pathways, 030104 developmental biology, Biotechnology & Applied Microbiology, chemistry, Biophysics, Chromatography, Gel, RNA Interference, Xylans, Agronomy and Crop Science, 010606 plant biology & botany, Biotechnology, Research Article
Abstract

International audience; Arabinoxylan (AX) is the dominant component within wheat (Triticum aestivum L.) endosperm cell walls, accounting for 70% of the polysaccharide. The viscosity of aqueous extracts from wheat grain is a key trait influencing the processing for various end uses, and this is largely determined by the properties of endosperm AX. We have previously shown dramatic effects on endosperm AX in transgenic wheat by down-regulating either TaGT43_2 or TaGT47_2 genes (orthologues to IRX9 and IRX10 in Arabidopsis, respectively) implicated in AX chain extension and the TaXAT1 gene responsible for monosubstitution by 3-linked arabinose. Here, we use these transgenic lines to investigate the relationship between amounts of AX in soluble and insoluble fractions, the chain-length distribution of these measured by intrinsic viscosity and the overall effect on extract viscosity. In transgenic lines expressing either the TaGT43_2 or TaGT47_2 RNAi transgenes, the intrinsic viscosities of water-extractable (WE-AX) and of a water-insoluble alkaline-extracted fraction (AE-AX) were decreased by between 10% and 50% compared to control lines. In TaXAT1 RNAi lines, there was a 15% decrease in intrinsic viscosity of WE-AX but no consistent effect on that of AE-AX. All transgenic lines showed decreases in extract viscosity with larger effects in TaGT43_2 and TaGT47_2 RNAi lines (by up to sixfold) than in TaXAT1 RNAi lines (by twofold). These effects were explained by the decreases in amount and chain length of WE-AX, with decreases in amount having the greater influence. Extract viscosity from wheat grain can therefore be greatly decreased by suppression of single gene targets.

Published
2014

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