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1. A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation.

Author

Llimos, Gerard, Gardeux, Vincent, Koch, Ute, Kribelbauer, Judith, Hafner, Antonina, Alpern, Daniel, Pezoldt, Joern, Litovchenko, Maria, Russeil, Julie, Dainese, Riccardo, Moia, Riccardo, Mahmoud, Abdurraouf, Rossi, Davide, Gaidano, Gianluca, Plass, Christoph, Lutsik, Pavlo, Gerhauser, Clarissa, Waszak, Sebastian, Boettiger, Alistair, Radtke, Freddy, and Deplancke, Bart

Subjects
Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Germ Cells, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Transcription Factors
Abstract

Non-coding variants coordinate transcription factor (TF) binding and chromatin mark enrichment changes over regions spanning >100 kb. These molecularly coordinated regions are named variable chromatin modules (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. To better understand the molecular mechanisms underlying VCM formation, here, we mechanistically dissect a VCM-modulating noncoding variant that is associated with reduced chronic lymphocytic leukemia (CLL) predisposition and disease progression. This common, germline variant constitutes a 5-bp indel that controls the activity of an AXIN2 gene-linked VCM by creating a MEF2 binding site, which, upon binding, activates a super-enhancer-like regulatory element. This triggers a large change in TF binding activity and chromatin state at an enhancer cluster spanning >150 kb, coinciding with subtle, long-range chromatin compaction and robust AXIN2 up-regulation. Our results support a model in which the indel acts as an AXIN2 VCM-activating TF nucleation event, which modulates CLL pathology.

Published
2022

2. Postnatal expansion of mesenteric lymph node stromal cells towards reticular and CD34+ stromal cell subsets

Author

Pezoldt, Joern, Wiechers, Carolin, Zou, Mangge, Litovchenko, Maria, Biocanin, Marjan, Beckstette, Michael, Sitnik, Katarzyna, Palatella, Martina, van Mierlo, Guido, Chen, Wanze, Gardeux, Vincent, Floess, Stefan, Ebel, Maria, Russeil, Julie, Arampatzi, Panagiota, Vafardanejad, Ehsan, Saliba, Antoine-Emmanuel, Deplancke, Bart, and Huehn, Jochen

Published
2022
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6. Body composition and lung cancer-associated cachexia in TRACERx

Author

Al-Sawaf, Othman, Weiss, Jakob, Skrzypski, Marcin, Lam, Jie Min, Karasaki, Takahiro, Zambrana, Francisco, Kidd, Andrew C, Frankell, Alexander M, Watkins, Thomas BK, Martinez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Huebner, Ariana, Al Bakir, Maise, Sokac, Mateo, Collins, Susie, Veeriah, Selvaraju, Magno, Neil, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Ward, Sophia, Jayanth, Nick, Salgado, Roberto, Bridge, Christopher P, Christiani, David C, Mak, Raymond H, Bay, Camden, Rosenthal, Michael, Sattar, Naveed, Welsh, Paul, Liu, Ying, Perrimon, Norbert, Popuri, Karteek, Beg, Mirza Faisal, McGranahan, Nicholas, Hackshaw, Allan, Breen, Danna M, O'Rahilly, Stephen, Birkbak, Nicolai J, Aerts, Hugo JWL, Jamal-Hanjani, Mariam, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Van Loo, Peter, Szallasi, Zoltan, Kisistok, Judit, Diossy, Miklos, Demeulemeester, Jonas, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Abbosh, Christopher, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Hiley, Crispin T, Moore, David A, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Cadieux, Elizabeth Larose, Lim, Emilia L, Colliver, Emma, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Hartley, John A, Peggs, Karl S, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Grigoriadis, Kristiana, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Hill, Mark S, Dietzen, Michelle, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Pich, Oriol, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Zaccaria, Simone, Hessey, Sonya, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

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

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

Published
2023

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

Author

Al Bakir, Maise, Huebner, Ariana, Martinez-Ruiz, Carlos, Grigoriadis, Kristiana, Watkins, Thomas BK, Pich, Oriol, Moore, David A, Veeriah, Selvaraju, Ward, Sophia, Laycock, Joanne, Johnson, Diana, Rowan, Andrew, Razaq, Maryam, Akther, Mita, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Hessey, Sonya, Dietzen, Michelle, Colliver, Emma, Frankell, Alexander, Bunkum, Abigail, Lim, Emilia L, Karasaki, Takahiro, Abbosh, Christopher, Hiley, Crispin T, Hill, Mark S, Cook, Daniel E, Wilson, Gareth A, Salgado, Roberto, Nye, Emma, Stone, Richard Kevin, Fennell, Dean A, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Summers, Yvonne, Lindsay, Colin R, Blackhall, Fiona H, Cave, Judith, Blyth, Kevin G, Nair, Arjun, Ahmed, Asia, Taylor, Magali N, Procter, Alexander James, Falzon, Mary, Lawrence, David, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Papadatos-Pastos, Dionysis, Forster, Martin D, Lee, Siow Ming, Ahmad, Tanya, Quezada, Sergio, Peggs, Karl S, Van Loo, Peter, Dive, Caroline, Hackshaw, Allan, Birkbak, Nicolai J, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Benafif, Sarah, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Krebs, Matthew G, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Puttick, Clare, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Black, James RM, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Clonal Evolution, Cohort Studies, Evolution, Molecular, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Disease Progression, Humans, Neoplasm Metastasis, Neoplasm Recurrence, Local, Clone Cells
Abstract

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

8. The evolution of lung cancer and impact of subclonal selection in TRACERx

Author

Frankell, Alexander M, Dietzen, Michelle, Al Bakir, Maise, Lim, Emilia L, Karasaki, Takahiro, Ward, Sophia, Veeriah, Selvaraju, Colliver, Emma, Huebner, Ariana, Bunkum, Abigail, Hill, Mark S, Grigoriadis, Kristiana, Moore, David A, Black, James RM, Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas BK, Naceur-Lombardelli, Cristina, Cook, Daniel E, Salgado, Roberto, Wilson, Gareth A, Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martinez-Ruiz, Carlos, Abbosh, Christopher, Nicholson, Andrew G, Le Quesne, John, Biswas, Dhruva, Rosenthal, Rachel, Puttick, Clare, Hessey, Sonya, Lee, Claudia, Prymas, Paulina, Toncheva, Antonia, Smith, Jon, Xing, Wei, Nicod, Jerome, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Blyth, Kevin G, Fennell, Dean A, Forster, Martin D, Lee, Siow Ming, Falzon, Mary, Hewish, Madeleine, Shackcloth, Michael J, Lim, Eric, Benafif, Sarah, Russell, Peter, Boleti, Ekaterini, Krebs, Matthew G, Lester, Jason F, Papadatos-Pastos, Dionysis, Ahmad, Tanya, Thakrar, Ricky M, Lawrence, David, Navani, Neal, Janes, Sam M, Dive, Caroline, Blackhall, Fiona H, Summers, Yvonne, Cave, Judith, Marafioti, Teresa, Herrero, Javier, Quezada, Sergio A, Peggs, Karl S, Schwarz, Roland F, Van Loo, Peter, Miedema, Daniel M, Birkbak, Nicolai J, Hiley, Crispin T, Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joa, Primrose, Lindsay, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Kaufmann, Tom L, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran L, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Rane, Jayant K, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Danson, Sarah, Robinson, Lily, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Lung Neoplasms, Treatment Outcome, DNA Copy Number Variations, Mutagenesis, Carcinoma, Non-Small-Cell Lung, Mutation, Smoking, Humans, Adenocarcinoma of Lung, Neoplasm Recurrence, Local, Phylogeny
Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

9. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Author

Karasaki, Takahiro, Moore, David A, Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Magno, Neil, Ward, Sophia, Al Bakir, Maise, Watkins, Thomas BK, Grigoriadis, Kristiana, Huebner, Ariana, Hill, Mark S, Frankell, Alexander M, Abbosh, Christopher, Puttick, Clare, Zhai, Haoran, Gimeno-Valiente, Francisco, Saghafinia, Sadegh, Kanu, Nnennaya, Dietzen, Michelle, Pich, Oriol, Lim, Emilia L, Martinez-Ruiz, Carlos, Black, James RM, Biswas, Dhruva, Campbell, Brittany B, Lee, Claudia, Colliver, Emma, Enfield, Katey SS, Hessey, Sonya, Hiley, Crispin T, Zaccaria, Simone, Litchfield, Kevin, Birkbak, Nicolai J, Cadieux, Elizabeth Larose, Demeulemeester, Jonas, Van Loo, Peter, Adusumilli, Prasad R, Tan, Kay See, Cheema, Waseem, Sanchez-Vega, Francisco, Jones, David R, Rekhtman, Natasha, Travis, William D, Hackshaw, Allan, Marafioti, Teresa, Salgado, Roberto, Le Quesne, John, Nicholson, Andrew G, McGranahan, Nicholas, Swanton, Charles, Jamal-Hanjani, Mariam, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Castignani, Carla, Bailey, Chris, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Peggs, Karl S, Selvaraju, Kayalvizhi, Thol, Kerstin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Prymas, Paulina, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
TRACERx Consortium
Abstract

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

Published
2023

13. Fly Cell Atlas: A single-nucleus transcriptomic atlas of the adult fruit fly

Author

Li, Hongjie, Janssens, Jasper, De Waegeneer, Maxime, Kolluru, Sai Saroja, Davie, Kristofer, Gardeux, Vincent, Saelens, Wouter, David, Fabrice P. A., Brbić, Maria, Spanier, Katina, Leskovec, Jure, McLaughlin, Colleen N., Xie, Qijing, Jones, Robert C., Brueckner, Katja, Shim, Jiwon, Tattikota, Sudhir Gopal, Schnorrer, Frank, Rust, Katja, Nystul, Todd G., Carvalho-Santos, Zita, Ribeiro, Carlos, Pal, Soumitra, Mahadevaraju, Sharvani, Przytycka, Teresa M., Allen, Aaron M., Goodwin, Stephen F., Berry, Cameron W., Fuller, Margaret T., White-Cooper, Helen, Matunis, Erika L., DiNardo, Stephen, Galenza, Anthony, O’Brien, Lucy Erin, Dow, Julian A. T., Jasper, Heinrich, Oliver, Brian, Perrimon, Norbert, Deplancke, Bart, Quake, Stephen R., Luo, Liqun, Aerts, Stein, Agarwal, Devika, Ahmed-Braimah, Yasir, Arbeitman, Michelle, Ariss, Majd M., Augsburger, Jordan, Ayush, Kumar, Baker, Catherine C., Banisch, Torsten, Birker, Katja, Bodmer, Rolf, Bolival, Benjamin, Brantley, Susanna E., Brill, Julie A., Brown, Nora C., Buehner, Norene A., Cai, Xiaoyu Tracy, Cardoso-Figueiredo, Rita, Casares, Fernando, Chang, Amy, Clandinin, Thomas R., Crasta, Sheela, Desplan, Claude, Detweiler, Angela M., Dhakan, Darshan B., Donà, Erika, Engert, Stefanie, Floc’hlay, Swann, George, Nancy, González-Segarra, Amanda J., Groves, Andrew K., Gumbin, Samantha, Guo, Yanmeng, Harris, Devon E., Heifetz, Yael, Holtz, Stephen L., Horns, Felix, Hudry, Bruno, Hung, Ruei-Jiun, Jan, Yuh Nung, Jaszczak, Jacob S., Jefferis, Gregory S. X. E., Karkanias, Jim, Karr, Timothy L., Katheder, Nadja Sandra, Kezos, James, Kim, Anna A., Kim, Seung K., Kockel, Lutz, Konstantinides, Nikolaos, Kornberg, Thomas B., Krause, Henry M., Labott, Andrew Thomas, Laturney, Meghan, Lehmann, Ruth, Leinwand, Sarah, Li, Jiefu, Li, Joshua Shing Shun, Li, Kai, Li, Ke, Li, Liying, Li, Tun, Litovchenko, Maria, Liu, Han-Hsuan, Liu, Yifang, Lu, Tzu-Chiao, Manning, Jonathan, Mase, Anjeli, Matera-Vatnick, Mikaela, Matias, Neuza Reis, McDonough-Goldstein, Caitlin E., McGeever, Aaron, McLachlan, Alex D., Moreno-Roman, Paola, Neff, Norma, Neville, Megan, Ngo, Sang, Nielsen, Tanja, O’Brien, Caitlin E., Osumi-Sutherland, David, Özel, Mehmet Neset, Papatheodorou, Irene, Petkovic, Maja, Pilgrim, Clare, Pisco, Angela Oliveira, Reisenman, Carolina, Sanders, Erin Nicole, dos Santos, Gilberto, Scott, Kristin, Sherlekar, Aparna, Shiu, Philip, Sims, David, Sit, Rene V., Slaidina, Maija, Smith, Harold E., Sterne, Gabriella, Su, Yu-Han, Sutton, Daniel, Tamayo, Marco, Tan, Michelle, Tastekin, Ibrahim, Treiber, Christoph, Vacek, David, Vogler, Georg, Waddell, Scott, Wang, Wanpeng, Wilson, Rachel I., Wolfner, Mariana F., Wong, Yiu-Cheung E., Xie, Anthony, Xu, Jun, Yamamoto, Shinya, Yan, Jia, Yao, Zepeng, Yoda, Kazuki, Zhu, Ruijun, Zinzen, Robert P., Howard Hughes Medical Institute, Department of Biology, Stanford University, Stanford, CA 94305, USA, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health (US), Stanford University, Howard Hughes Medical Institute, KU Leuven, Flemish Department of Economy, Science and Innovation (Belgium), and Consortium, FCA

Subjects
Cell Nucleus, Male, Sex Characteristics, Multidisciplinary, [SDV.BA]Life Sciences [q-bio]/Animal biology, fungi, Genes, Insect, Article, Drosophila melanogaster, Gene Expression Regulation, Databases, Genetic, Animals, Drosophila Proteins, Female, Gene Regulatory Networks, RNA-Seq, Single-Cell Analysis, Transcriptome, Transcription Factors
Abstract

FCA Consortium: Stein Aerts, Devika Agarwal, Yasir Ahmed-Braimah, Aaron M. Allen, Michelle Arbeitman, Majd M. Ariss, Jordan Augsburger, Kumar Ayush, Catherine C. Baker, Torsten Banisch, Cameron W. Berry, Katja Birker, Rolf Bodmer, Benjamin Bolival, Susanna E. Brantley, Maria Brbić, Julie A. Brill, Nora C. Brown, Katja Brueckner, Norene A. Buehner, Xiaoyu Tracy Cai, Rita Cardoso-Figueiredo, Zita Carvalho-Santos, Casares,Fernando, Amy Chang, Thomas R. Clandinin, Sheela Crasta, Fabrice P. A. David, Kristofer Davie4, Bart Deplancke, Claude Desplan44, Angela M. Detweiler, Darshan B. Dhakan, Stephen DiNardo, Erika Donà, Julian A. T. Dow, Stefanie Engert, Swann Floc’hlay, Margaret T. Fuller, Anthony Galenza, Vincent Gardeux, Nancy George, Amanda J. González-Segarra, Stephen F. Goodwin, Andrew K. Groves, Samantha Gumbin Yanmeng Guo, Devon E. Harris, Yael Heifetz, Stephen L. Holtz, Felix Horns, Bruno Hudry, Ruei-Jiun Hung, Yuh Nung Jan, Jasper Janssens, Heinrich Jasper, Jacob S. Jaszczak, Gregory S. X. E. Jefferis, Robert C. Jones, Jim Karkanias, Timothy L. Karr, Nadja Sandra Katheder, James Kezos, Anna A. Kim, Seung K. Kim, Lutz Kockel, Sai Saroja Kolluru6,7,8, Nikolaos Konstantinides, Thomas B. Kornberg, Henry M. Krause, Andrew Thomas Labott, Meghan Laturney, Ruth Lehmann, Sarah Leinwand, Jure Leskovec, Hongjie Li1, Jiefu Li1, Joshua Shing Shun Li, Kai Li, Ke Li, Liying Li, Tun Li, Maria Litovchenko, Han-Hsuan Liu, Yifang Liu, Tzu-Chiao Lu, Liqun Luo, Sharvani Mahadevaraju, Jonathan Manning, Anjeli Mase, Mikaela Matera-Vatnick, Neuza Reis Matias, Erika L. Matunis, Caitlin E. McDonough-Goldstein, Aaron McGeever, Alex D. McLachlan, Colleen N. McLaughlin, Paola Moreno-Roman, Norma Neff, Megan Neville, Sang Ngo, Tanja Nielsen, Todd G. Nystul, Caitlin E. O’Brien, Lucy Erin O’Brien, Brian Oliver, David Osumi-Sutherland, Mehmet Neset Özel, Soumitra Pal, Irene Papatheodorou, Norbert Perrimon, Maja Petkovic, Clare Pilgrim68, Angela Oliveira Pisco, Teresa M. Przytycka, Stephen R. Quake, Carolina Reisenman, Carlos Ribeiro, Katja Rust, Wouter Saelens, Erin Nicole Sanders, Gilberto dos Santos, Frank Schnorrer, Kristin Scott, Aparna Sherlekar, Jiwon Shim, Philip Shiu, David Sims, Rene V. Sit, Maija Slaidina, Harold E. Smith, Katina Spanier, Gabriella Sterne, Yu-Han Su, Daniel Sutton, Marco Tamayo, Michelle Tan, Ibrahim Tastekin, Sudhir Gopal Tattikota, Christoph Treiber, David Vacek, Georg Vogler, Scott Waddell, Maxime De Waegeneer, Wanpeng Wang, Helen White-Cooper, Rachel I. Wilson, Mariana F. Wolfner, Yiu-Cheung E. Wong, Anthony Xie, Qijing Xie, Jun Xu, Shinya Yamamoto, Jia Yan, Zepeng Yao, Kazuki Yodaformat , Ruijun Zhu, Robert P. Zinzen, For more than 100 years, the fruit fly Drosophila melanogaster has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula Drosophilae, that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type–related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the Drosophila community and serves as a reference to study genetic perturbations and disease models at single-cell resolution., The sequencing was supported by the Chan Zuckerberg Biohub (S.R.Q.), Genentech Inc. (H.J.), National Institutes of Health intramural 1ZIADK015600 (B.O.), national funds through the FCT in the framework of the financing of the Norma Transitória DL 57/2016 (Z.C.-S.), Wu Tsai Neurosciences Institute at Stanford (S.R.Q. and L.L.), and the Howard Hughes Medical Institute and a National Institutes of Health grant (L.L.). Computational work was supported by the KU Leuven and the Flemish Supercomputer Center (VSC) (S.A.) and EPFL (B.D.). FCA Consortium funding is provided in the supplementary materials.

Published
2022

15. A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation

Author

Llimos, Gerard, Gardeux, Vincent, Koch, Ute, Kribelbauer, Judith F., Hafner, Antonina, Alpern, Daniel, Pezoldt, Joern, Litovchenko, Maria, Russeil, Julie, Dainese, Riccardo, Moia, Riccardo, Mahmoud, Abdurraouf Mokhtar, Rossi, Davide, Gaidano, Gianluca, Plass, Christoph, Lutsik, Pavlo, Gerhauser, Clarissa, Waszak, Sebastian Martin, Boettiger, Alistair, Radtke, Freddy, and Deplancke, Bart

Subjects
Enhancer Elements, Genetic, Germ Cells, Gene Expression Regulation, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Chromatin, Transcription Factors
Abstract

Non-coding variants coordinate transcription factor (TF) binding and chromatin mark enrichment changes over regions spanning >100 kb. These molecularly coordinated regions are named "variable chromatin modules" (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. To better understand the molecular mechanisms underlying VCM formation, here, we mechanistically dissect a VCM-modulating noncoding variant that is associated with reduced chronic lymphocytic leukemia (CLL) predisposition and disease progression. This common, germline variant constitutes a 5-bp indel that controls the activity of an AXIN2 gene-linked VCM by creating a MEF2 binding site, which, upon binding, activates a super-enhancer-like regulatory element. This triggers a large change in TF binding activity and chromatin state at an enhancer cluster spanning >150 kb, coinciding with subtle, long-range chromatin compaction and robust AXIN2 up-regulation. Our results support a model in which the indel acts as an AXIN2 VCM-activating TF nucleation event, which modulates CLL pathology., Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia.

Published
2021

17. Postnatal lymph node expansion of stromal progenitors towards reticular and CD34+ stromal cell subsets is determined by distinct transcriptional programs

Author

Pezoldt, Joern, primary, Wiechrs, Carolin, additional, Litovchenko, Maria, additional, Biočanin, Marjan, additional, Zou, Mangge, additional, Sitnik, Katarzyna, additional, Beckstette, Michael, additional, Chen, Wanze, additional, Gardeux, Vincent, additional, Floess, Stefan, additional, Ebel, Maria, additional, Russeil, Julie, additional, Arampatzi, Panagiota, additional, Vafardanejad, Ehsan, additional, Saliba, Antoine-Emmanuel, additional, Deplancke, Bart, additional, and Huehn, Jochen, additional

Published
2021
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18. Postnatal lymph node expansion of stromal progenitors towards reticular and CD34+stromal cell subsets is determined by distinct transcriptional programs

Author

Pezoldt, Joern, primary, Wiechers, Carolin, additional, Litovchenko, Maria, additional, Biocanin, Marjan, additional, Zou, Mangge, additional, Sitnik, Katarzyna, additional, Beckstette, Michael, additional, Chen, Wanze, additional, Gardeux, Vincent, additional, Floess, Stefan, additional, Ebel, Maria, additional, Russeil, Julie, additional, Arampatzi, Panagiota, additional, Vafardanejad, Ehsan, additional, Saliba, Antoine-Emmanuel, additional, Deplancke, Bart, additional, and Huehn, Jochen, additional

Published
2021
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20. Extensive tissue-specific expression variation and novel regulators underlying circadian behavior

Author

Litovchenko, Maria, primary, Meireles-Filho, Antonio C. A., additional, Frochaux, Michael V., additional, Bevers, Roel P. J., additional, Prunotto, Alessio, additional, Anduaga, Ane Martin, additional, Hollis, Brian, additional, Gardeux, Vincent, additional, Braman, Virginie S., additional, Russeil, Julie M. C., additional, Kadener, Sebastian, additional, dal Peraro, Matteo, additional, and Deplancke, Bart, additional

Published
2021
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21. MOESM1 of cis-regulatory variation modulates susceptibility to enteric infection in the Drosophila genetic reference panel

Author

Frochaux, Michael, Sleiman, Maroun Bou, Gardeux, Vincent, Dainese, Riccardo, Hollis, Brian, Litovchenko, Maria, Braman, Virginie, Andreani, Tommaso, Osman, Dani, and Deplancke, Bart

Abstract

Additional file 1: Figure S1. Reproducibility of line-specific transcriptomes. Figure S2. Analysis of several ntc mutants. Figure S3. Relationship between minor allele frequency and condition-specific local-eQTLs. Figure S4. Quality control of BRB-seq libraries. Figure S5. Comparison between TruSeq and BRB-seq libraries. Figure S6. Comparison of measured local-eQTL effect size and cis-eQTL effect size. Figure S7. MITOMI analysis of distinct TFs associated with the ntc locus.

Published
2020
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26. Bayesian association scan reveals loci associated with human lifespan and linked biomarkers

Author

McDaid, Aaron F., primary, Joshi, Peter K., additional, Porcu, Eleonora, additional, Komljenovic, Andrea, additional, Li, Hao, additional, Sorrentino, Vincenzo, additional, Litovchenko, Maria, additional, Bevers, Roel P. J., additional, Rüeger, Sina, additional, Reymond, Alexandre, additional, Bochud, Murielle, additional, Deplancke, Bart, additional, Williams, Robert W., additional, Robinson-Rechavi, Marc, additional, Paccaud, Fred, additional, Rousson, Valentin, additional, Auwerx, Johan, additional, Wilson, James F., additional, and Kutalik, Zoltán, additional

Published
2017
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32. cis-regulatory variation modulates susceptibility to enteric infection in the Drosophilagenetic reference panel

Author

Frochaux, Michael V., Bou Sleiman, Maroun, Gardeux, Vincent, Dainese, Riccardo, Hollis, Brian, Litovchenko, Maria, Braman, Virginie S., Andreani, Tommaso, Osman, Dani, and Deplancke, Bart

Abstract

Background: Resistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes. We have previously shown in the DrosophilaGenetic Reference Panel (DGRP) that resistance to infection is highly heritable, but our understanding of how the effects of genetic variants affect different molecular mechanisms to determine gut immunocompetence is still limited. Results: To address this, we perform a systems genetics analysis of the gut transcriptomes from 38 DGRP lines that were orally infected with Pseudomonas entomophila. We identify a large number of condition-specific, expression quantitative trait loci (local-eQTLs) with infection-specific ones located in regions enriched for FOX transcription factor motifs. By assessing the allelic imbalance in the transcriptomes of 19 F1 hybrid lines from a large round robin design, we independently attribute a robust cis-regulatory effect to only 10% of these detected local-eQTLs. However, additional analyses indicate that many local-eQTLs may act in transinstead. Comparison of the transcriptomes of DGRP lines that were either susceptible or resistant to Pseudomonas entomophilainfection reveals nutcrackeras the only differentially expressed gene. Interestingly, we find that nutcrackeris linked to infection-specific eQTLs that correlate with its expression level and to enteric infection susceptibility. Further regulatory analysis reveals one particular eQTL that significantly decreases the binding affinity for the repressor Broad, driving differential allele-specific nutcrackerexpression. Conclusions: Our collective findings point to a large number of infection-specific cis-and trans-acting eQTLs in the DGRP, including one common non-coding variant that lowers enteric infection susceptibility.

Published
2020
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33. Mitochondrial haplotypes affect metabolic phenotypes in the Drosophila Genetic Reference Panel

Author

Bevers, Roel P. J., Litovchenko, Maria, Kapopoulou, Adamandia, Braman, Virginie S., Robinson, Matthew R., Auwerx, Johan, Hollis, Brian, and Deplancke, Bart

Subjects
melanogaster, epistasis, mtdna, genotype, flies, genome-wide association, oxidative stress, selection, program, polymorphism
Abstract

The nature and extent of mitochondrial DNA variation in a population and how it affects traits is poorly understood. Here we resequence the mitochondrial genomes of 169 Drosophila Genetic Reference Panel lines, identifying 231 variants that stratify along 12 mitochondrial haplotypes. We identify 1,845 cases of mitonuclear allelic imbalances, thus implying that mitochondrial haplotypes are reflected in the nuclear genome. However, no major fitness effects are associated with mitonuclear imbalance, suggesting that such imbalances reflect population structure at the mitochondrial level rather than genomic incompatibilities. Although mitochondrial haplotypes have no direct impact on mitochondrial respiration, some haplotypes are associated with stress- and metabolism-related phenotypes, including food intake in males. Finally, through reciprocal swapping of mitochondrial genomes, we demonstrate that a mitochondrial haplotype associated with high food intake can rescue a low food intake phenotype. Together, our findings provide new insight into population structure at the mitochondrial level and point to the importance of incorporating mitochondrial haplotypes in genotype-phenotype relationship studies.

34. Extensive tissue-specific expression variation and novel regulators underlying circadian behavior

Author

Litovchenko, Maria, Meireles-Filho, Antonio C. A., Frochaux, Michael, V, Bevers, Roel P. J., Prunotto, Alessio, Anduaga, Ane Martin, Hollis, Brian, Gardeux, Vincent, Braman, Virginie S., Russeil, Julie M. C., Kadener, Sebastian, dal Peraro, Matteo, and Deplancke, Bart

Abstract

Natural genetic variation affects circadian rhythms across the evolutionary tree, but the underlying molecular mechanisms are poorly understood. We investigated population-level, molecular circadian clock variation by generating >700 tissue-specific transcriptomes of Drosophila melanogaster (w(1118)) and 141 Drosophila Genetic Reference Panel (DGRP) lines. This comprehensive circadian gene expression atlas contains >1700 cycling genes including previously unknown central circadian clock components and tissue-specific regulators. Furthermore, >30% of DGRP lines exhibited aberrant circadian gene expression, revealing abundant genetic variation-mediated, intertissue circadian expression desynchrony. Genetic analysis of one line with the strongest deviating circadian expression uncovered a novel cry mutation that, as shown by protein structural modeling and brain immunohistochemistry, disrupts the light-driven flavin adenine dinucleotide cofactor photoreduction, providing in vivo support for the importance of this conserved photoentrainment mechanism. Together, our study revealed pervasive tissue-specific circadian expression variation with genetic variants acting upon tissue-specific regulatory networks to generate local gene expression oscillations.

35. Fly Cell Atlas: A single-nucleus transcriptomic atlas of the adult fruit fly.

Author

Li H, Janssens J, De Waegeneer M, Kolluru SS, Davie K, Gardeux V, Saelens W, David FPA, Brbić M, Spanier K, Leskovec J, McLaughlin CN, Xie Q, Jones RC, Brueckner K, Shim J, Tattikota SG, Schnorrer F, Rust K, Nystul TG, Carvalho-Santos Z, Ribeiro C, Pal S, Mahadevaraju S, Przytycka TM, Allen AM, Goodwin SF, Berry CW, Fuller MT, White-Cooper H, Matunis EL, DiNardo S, Galenza A, O'Brien LE, Dow JAT, Jasper H, Oliver B, Perrimon N, Deplancke B, Quake SR, Luo L, Aerts S, Agarwal D, Ahmed-Braimah Y, Arbeitman M, Ariss MM, Augsburger J, Ayush K, Baker CC, Banisch T, Birker K, Bodmer R, Bolival B, Brantley SE, Brill JA, Brown NC, Buehner NA, Cai XT, Cardoso-Figueiredo R, Casares F, Chang A, Clandinin TR, Crasta S, Desplan C, Detweiler AM, Dhakan DB, Donà E, Engert S, Floc'hlay S, George N, González-Segarra AJ, Groves AK, Gumbin S, Guo Y, Harris DE, Heifetz Y, Holtz SL, Horns F, Hudry B, Hung RJ, Jan YN, Jaszczak JS, Jefferis GSXE, Karkanias J, Karr TL, Katheder NS, Kezos J, Kim AA, Kim SK, Kockel L, Konstantinides N, Kornberg TB, Krause HM, Labott AT, Laturney M, Lehmann R, Leinwand S, Li J, Li JSS, Li K, Li K, Li L, Li T, Litovchenko M, Liu HH, Liu Y, Lu TC, Manning J, Mase A, Matera-Vatnick M, Matias NR, McDonough-Goldstein CE, McGeever A, McLachlan AD, Moreno-Roman P, Neff N, Neville M, Ngo S, Nielsen T, O'Brien CE, Osumi-Sutherland D, Özel MN, Papatheodorou I, Petkovic M, Pilgrim C, Pisco AO, Reisenman C, Sanders EN, Dos Santos G, Scott K, Sherlekar A, Shiu P, Sims D, Sit RV, Slaidina M, Smith HE, Sterne G, Su YH, Sutton D, Tamayo M, Tan M, Tastekin I, Treiber C, Vacek D, Vogler G, Waddell S, Wang W, Wilson RI, Wolfner MF, Wong YE, Xie A, Xu J, Yamamoto S, Yan J, Yao Z, Yoda K, Zhu R, and Zinzen RP

Subjects
Animals, Cell Nucleus metabolism, Databases, Genetic, Drosophila Proteins genetics, Drosophila melanogaster physiology, Female, Gene Expression Regulation, Gene Regulatory Networks, Genes, Insect, Male, RNA-Seq, Sex Characteristics, Single-Cell Analysis, Transcription Factors genetics, Drosophila melanogaster cytology, Drosophila melanogaster genetics, Transcriptome
Abstract

For more than 100 years, the fruit fly Drosophila melanogaster has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula Drosophilae , that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the Drosophila community and serves as a reference to study genetic perturbations and disease models at single-cell resolution.

Published
2022
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