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1. Author Correction: Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting

Author

Prosz, Aurel, Sahgal, Pranshu, Huffman, Brandon M., Sztupinszki, Zsofia, Morris, Clare X., Chen, David, Börcsök, Judit, Diossy, Miklos, Tisza, Viktoria, Spisak, Sandor, Likasitwatanakul, Pornlada, Rusz, Orsolya, Csabai, Istvan, Cecchini, Michael, Baca, Yasmine, Elliott, Andrew, Enzinger, Peter, Singh, Harshabad, Ubellaker, Jessalyn, Lazaro, Jean-Bernard, Cleary, James M., Szallasi, Zoltan, and Sethi, Nilay S.

Published
2024
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2. Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting

Author

Prosz, Aurel, Sahgal, Pranshu, Huffman, Brandon M., Sztupinszki, Zsofia, Morris, Clare X., Chen, David, Börcsök, Judit, Diossy, Miklos, Tisza, Viktoria, Spisak, Sandor, Likasitwatanakul, Pornlada, Rusz, Orsolya, Csabai, Istvan, Cecchini, Michael, Baca, Yasmine, Elliott, Andrew, Enzinger, Peter, Singh, Harshabad, Ubellaker, Jessalyn, Lazaro, Jean-Bernard, Cleary, James M., Szallasi, Zoltan, and Sethi, Nilay S.

Published
2024
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3. Liquid biopsy epigenomic profiling for cancer subtyping

Author

Baca, Sylvan C., Seo, Ji-Heui, Davidsohn, Matthew P., Fortunato, Brad, Semaan, Karl, Sotudian, Shahabbedin, Lakshminarayanan, Gitanjali, Diossy, Miklos, Qiu, Xintao, El Zarif, Talal, Savignano, Hunter, Canniff, John, Madueke, Ikenna, Saliby, Renee Maria, Zhang, Ziwei, Li, Rong, Jiang, Yijia, Taing, Len, Awad, Mark, Chau, Cindy H., DeCaprio, James A., Figg, William D., Greten, Tim F., Hata, Aaron N., Hodi, F. Stephen, Hughes, Melissa E., Ligon, Keith L., Lin, Nancy, Ng, Kimmie, Oser, Matthew G., Meador, Catherine, Parsons, Heather A., Pomerantz, Mark M., Rajan, Arun, Ritz, Jerome, Thakuria, Manisha, Tolaney, Sara M., Wen, Patrick Y., Long, Henry, Berchuck, Jacob E., Szallasi, Zoltan, Choueiri, Toni K., and Freedman, Matthew L.

Published
2023
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4. Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma

Author

Prosz, Aurel, Duan, Haohui, Tisza, Viktoria, Sahgal, Pranshu, Topka, Sabine, Klus, Gregory T., Börcsök, Judit, Sztupinszki, Zsofia, Hanlon, Timothy, Diossy, Miklos, Vizkeleti, Laura, Stormoen, Dag Rune, Csabai, Istvan, Pappot, Helle, Vijai, Joseph, Offit, Kenneth, Ried, Thomas, Sethi, Nilay, Mouw, Kent W., Spisak, Sandor, Pathania, Shailja, and Szallasi, Zoltan

Published
2023
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5. Author Correction: Liquid biopsy epigenomic profiling for cancer subtyping

Author

Baca, Sylvan C., Seo, Ji-Heui, Davidsohn, Matthew P., Fortunato, Brad, Semaan, Karl, Sotudian, Shahabbedin, Lakshminarayanan, Gitanjali, Diossy, Miklos, Qiu, Xintao, El Zarif, Talal, Savignano, Hunter, Canniff, John, Madueke, Ikenna, Saliby, Renee Maria, Zhang, Ziwei, Li, Rong, Jiang, Yijia, Taing, Len, Awad, Mark, Chau, Cindy H., DeCaprio, James A., Figg, William D., Greten, Tim F., Hata, Aaron N., Hodi, F. Stephen, Hughes, Melissa E., Ligon, Keith L., Lin, Nancy, Ng, Kimmie, Oser, Matthew G., Meador, Catherine, Parsons, Heather A., Pomerantz, Mark M., Rajan, Arun, Ritz, Jerome, Thakuria, Manisha, Tolaney, Sara M., Wen, Patrick Y., Long, Henry, Berchuck, Jacob E., Szallasi, Zoltan, Choueiri, Toni K., and Freedman, Matthew L.

Published
2024
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7. Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression without inducing homologous recombination deficiency

Author

Szallasi, Zoltan, primary, Diossy, Miklos, additional, Tisza, Viktoria, additional, Li, Hua, additional, Sahgal, Pranshu, additional, Zhou, Jia, additional, Sztupinszki, Zsofia, additional, Young, Denise, additional, Nuosome, Darryl, additional, Kuo, Claire, additional, Jiang, Jiji, additional, Chen, Yongmei, additional, Ebner, Reinhard, additional, Sesterhenn, Isabell, additional, Moncur, Joel, additional, Chesnut, Gregory, additional, Petrovics, Gyorgy, additional, T.Klus, Gregory, additional, Valcz, Gábor, additional, Nuzzo, Pier, additional, Ribli, Dezso, additional, Börcsök, Judit, additional, Prósz, Aurél, additional, Krzystanek, Marcin, additional, Ried, Thomas, additional, Szüts, Dávid, additional, Rizwan, Kinza, additional, Kaochar, Salma, additional, Pathania, Shailja, additional, D'Andrea, Alan, additional, Csabai, István, additional, Srivast, Shib, additional, Freedman, Matthew, additional, Dobi, Albert, additional, and Spisak, Sandor, additional

Published
2024
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8. Author Correction: Liquid biopsy epigenomic profiling for cancer subtyping

Author

Baca, Sylvan C., primary, Seo, Ji-Heui, additional, Davidsohn, Matthew P., additional, Fortunato, Brad, additional, Semaan, Karl, additional, Sotudian, Shahabbedin, additional, Lakshminarayanan, Gitanjali, additional, Diossy, Miklos, additional, Qiu, Xintao, additional, El Zarif, Talal, additional, Savignano, Hunter, additional, Canniff, John, additional, Madueke, Ikenna, additional, Saliby, Renee Maria, additional, Zhang, Ziwei, additional, Li, Rong, additional, Jiang, Yijia, additional, Taing, Len, additional, Awad, Mark, additional, Chau, Cindy H., additional, DeCaprio, James A., additional, Figg, William D., additional, Greten, Tim F., additional, Hata, Aaron N., additional, Hodi, F. Stephen, additional, Hughes, Melissa E., additional, Ligon, Keith L., additional, Lin, Nancy, additional, Ng, Kimmie, additional, Oser, Matthew G., additional, Meador, Catherine, additional, Parsons, Heather A., additional, Pomerantz, Mark M., additional, Rajan, Arun, additional, Ritz, Jerome, additional, Thakuria, Manisha, additional, Tolaney, Sara M., additional, Wen, Patrick Y., additional, Long, Henry, additional, Berchuck, Jacob E., additional, Szallasi, Zoltan, additional, Choueiri, Toni K., additional, and Freedman, Matthew L., additional

Published
2023
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10. 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

11. 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

12. 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

13. 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

14. Supplementary Data from Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations

Author

Sztupinszki, Zsofia, primary, Diossy, Miklos, primary, Krzystanek, Marcin, primary, Borcsok, Judit, primary, Pomerantz, Mark M., primary, Tisza, Viktoria, primary, Spisak, Sandor, primary, Rusz, Orsolya, primary, Csabai, István, primary, Freedman, Matthew L., primary, and Szallasi, Zoltan, primary

Published
2023
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18. Supplementary Data from Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer

Author

Börcsök, Judit, primary, Sztupinszki, Zsofia, primary, Bekele, Raie, primary, Gao, Sizhi P., primary, Diossy, Miklos, primary, Samant, Amruta S., primary, Dillon, Kasia M., primary, Tisza, Viktoria, primary, Spisák, Sándor, primary, Rusz, Orsolya, primary, Csabai, Istvan, primary, Pappot, Helle, primary, Frazier, Zoë J., primary, Konieczkowski, David J., primary, Liu, David, primary, Vasani, Naresh, primary, Rodrigues, James A., primary, Solit, David B., primary, Hoffman-Censits, Jean H., primary, Plimack, Elizabeth R., primary, Rosenberg, Jonathan E., primary, Lazaro, Jean-Bernard, primary, Taplin, Mary-Ellen, primary, Iyer, Gopa, primary, Brunak, Søren, primary, Lozsa, Rita, primary, Van Allen, Eliezer M., primary, Szüts, Dávid, primary, Mouw, Kent W., primary, and Szallasi, Zoltan, primary

Published
2023
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20. Supplementary Methods from Detection of Molecular Signatures of Homologous Recombination Deficiency in Bladder Cancer

Author

Börcsök, Judit, primary, Diossy, Miklos, primary, Sztupinszki, Zsofia, primary, Prosz, Aurel, primary, Tisza, Viktoria, primary, Spisak, Sandor, primary, Rusz, Orsolya, primary, Stormoen, Dag R., primary, Pappot, Helle, primary, Csabai, Istvan, primary, Brunak, Søren, primary, Mouw, Kent W., primary, and Szallasi, Zoltan, primary

Published
2023
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22. Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma

Author

Prosz, Aurel, primary, Duan, Haohui, additional, Tisza, Viktoria, additional, Sahgal, Pranshu, additional, Topka, Sabine, additional, Klus, Gregory T., additional, Börcsök, Judit, additional, Sztupinszki, Zsofia, additional, Hanlon, Timothy, additional, Diossy, Miklos, additional, Vizkeleti, Laura, additional, Stormoen, Dag Rune, additional, Csabai, Istvan, additional, Pappot, Helle, additional, Vijai, Joseph, additional, Offit, Kenneth, additional, Ried, Thomas, additional, Sethi, Nilay, additional, Mouw, Kent W., additional, Spisak, Sandor, additional, Pathania, Shailja, additional, and Szallasi, Zoltan, additional

Published
2023
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23. Diagnostic tool to identify and treat DNA repair deficient gastroesophageal adenocarcinomas

Author

Prosz, Aurel, primary, Sahgal, Pranshu, additional, Morris, Clare X, additional, Sztupinszki, Zsofia, additional, Borcsok, Judit, additional, Diossy, Miklos, additional, Tisza, Viktoria, additional, Spisak, Sandor, additional, Rusz, Orsolya, additional, Csabai, Istvan, additional, Huffman, Brandon M, additional, Singh, Harshabad, additional, Lazaro, Jean-Bernard, additional, Cecchini, Michael, additional, Cleary, James M, additional, Szallasi, Zoltan, additional, and Sethi, Nilay S, additional

Published
2022
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27. Detection of Molecular Signatures of Homologous Recombination Deficiency in Bladder Cancer

Author

Börcsök, Judit, primary, Diossy, Miklos, additional, Sztupinszki, Zsofia, additional, Prosz, Aurel, additional, Tisza, Viktoria, additional, Spisak, Sandor, additional, Rusz, Orsolya, additional, Stormoen, Dag R., additional, Pappot, Helle, additional, Csabai, Istvan, additional, Brunak, Søren, additional, Mouw, Kent W., additional, and Szallasi, Zoltan, additional

Published
2021
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28. SubclonalCHD1deletion is more frequent in African American prostate cancers and associated with rapid disease progression and limited levels of homologous recombination deficiency

Author

Diossy, Miklos, primary, Tisza, Viktoria, additional, Li, Hua, additional, Zhou, Jia, additional, Sztupinszki, Zsofia, additional, Young, Denise, additional, Nousome, Darryl, additional, Kuo, Claire, additional, Jiang, Jiji, additional, Chen, Yongmei, additional, Ebner, Reinhard, additional, Sesterhenn, Isabell A., additional, Moncur, Joel T., additional, Chesnut, Gregory T., additional, Petrovics, Gyorgy, additional, Klus, Gregory T., additional, Valcz, Gabor, additional, Nuzzo, Pier Vitale, additional, Ribli, Dezso, additional, Schina, Aimilia, additional, Börcsök, Judit, additional, Prosz, Aurel, additional, Krzystanek, Marcin, additional, Ried, Thomas, additional, Szuts, David, additional, Kaochar, Salma, additional, Pathania, Shailja, additional, D’Andrea, Alan D., additional, Csabai, Istvan, additional, Srivastava, Shiv, additional, Freedman, Matthew L, additional, Dobi, Albert, additional, Spisak, Sandor, additional, and Szallasi, Zoltan, additional

Published
2021
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29. Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer

Author

Börcsök, Judit, primary, Sztupinszki, Zsofia, additional, Bekele, Raie, additional, Gao, Sizhi P., additional, Diossy, Miklos, additional, Samant, Amruta S., additional, Dillon, Kasia M., additional, Tisza, Viktoria, additional, Spisák, Sándor, additional, Rusz, Orsolya, additional, Csabai, Istvan, additional, Pappot, Helle, additional, Frazier, Zoë J., additional, Konieczkowski, David J., additional, Liu, David, additional, Vasani, Naresh, additional, Rodrigues, James A., additional, Solit, David B., additional, Hoffman-Censits, Jean H., additional, Plimack, Elizabeth R., additional, Rosenberg, Jonathan E., additional, Lazaro, Jean-Bernard, additional, Taplin, Mary-Ellen, additional, Iyer, Gopa, additional, Brunak, Søren, additional, Lozsa, Rita, additional, Van Allen, Eliezer M., additional, Szüts, Dávid, additional, Mouw, Kent W., additional, and Szallasi, Zoltan, additional

Published
2020
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30. Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations

Author

Sztupinszki, Zsofia, primary, Diossy, Miklos, additional, Krzystanek, Marcin, additional, Borcsok, Judit, additional, Pomerantz, Mark M., additional, Tisza, Viktoria, additional, Spisak, Sandor, additional, Rusz, Orsolya, additional, Csabai, István, additional, Freedman, Matthew L., additional, and Szallasi, Zoltan, additional

Published
2020
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31. BRCA1/Trp53 heterozygosity and replication stress drive esophageal cancer development in a mouse model.

Author

Ye He, Rivera, Joshua, Diossy, Miklos, Haohui Duan, Bowman-Colin, Christian, Reed, Rachel, Jennings, Rebecca, Novak, Jesse, Tran, Stevenson V., Cohen, Elizabeth F., Szuts, David, Giobbie-Hurder, Anita, Bronson, Roderick T., Bass, Adam J., Signoretti, Sabina, Szallasi, Zoltan, Livingston, David M., and Pathania, Shailja

Subjects
LABORATORY mice, CARCINOGENESIS, ESOPHAGEAL cancer, ANIMAL disease models, HETEROZYGOSITY
Abstract

BRCA1 germline mutations are associated with an increased risk of breast and ovarian cancer. Recent findings of others suggest that BRCA1 mutation carriers also bear an increased risk of esophageal and gastric cancer. Here, we employ a Brca1/Trp53 mouse model to show that unresolved replication stress (RS) in BRCA1 heterozygous cells drives esophageal tumorigenesis in a model of the human equivalent. This model employs 4-nitroquinoline-1-oxide (4NQO) as an RS-inducing agent. Upon drinking 4NQO-containing water, Brca1 heterozygous mice formed squamous cell carcinomas of the distal esophagus and forestomach at a much higher frequency and speed (~90 to 120 d) than did wild-type (WT) mice, which remained largely tumor free. Their esophageal tissue, but not that of WT control mice, revealed evidence of overt RS as reflected by intracellular CHK1 phosphorylation and 53BP1 staining. These Brca1 mutant tumors also revealed higher genome mutation rates than those of control animals; the mutational signature SBS4, which is associated with tobacco-induced tumorigenesis; and a loss of Brca1 heterozygosity (LOH). This uniquely accelerated Brca1 tumor model is also relevant to human esophageal squamous cell carcinoma, an often lethal tumor. [ABSTRACT FROM AUTHOR]

Published
2021
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32. DNA Repair Pathway Aberrations in Personalized Chemotherapy

Author

Diossy, Miklos

Abstract

The utopian balance between the individual cells of meta-organism, such as humans, is maintained by a sophisticated web of regulatory mechanisms, that are the results of at least 3.5 billion years of Darwinian evolution. The complexity of these mechanisms is what makes the study of living organisms and life in general a fascinating pursuit, but it is also the main cause why we could not find an ultimate cure against cancer, this ancient disease yet. Due to the vast number of varying pathways comprising the regulatory machinery, a healthy cell may follow multiple directions to reach the state of malignancy, which makes cancer one of the most complex diseases, humanity ever had to face. Over the past few decades, however, due to the advancements in DNA sequencing technologies, we have made a significant progress towards the understanding of its underlying biological processes.Meticulous studies of the genome of malignant cells have revealed, that some of their genetic and epigenetic alterations can be utilized as specific targets against them. These strategies involve the usage of phenotypical changes, that are induced by these alterations, in targeted therapies, or to help the immune system of their host to target cancer epitopes displayed on their surface. The work presented in this thesis can be separated into a technical and exploratory part. Exploratory projects focus on the identification of deficiencies in the homologous recombination (HR) double-strand break (DSB) repair pathway through the detection of genetic markers of HR-deficiency (HRD). Technical manuscripts, on the other hand, aim to resolve analytical issues that may distort the detectability of these markers. Part I of the thesis is a general introduction to cancer genomics and its related fields. It is meant to summarize my understanding of the topic, and to describe all the features and concepts that are necessary to comprehend the contents of the manuscripts that comprise Part II.The first biomarkers of HR-deficiency that relied on large scale genomic scars have been developed on microarray data, and it was debatable whether they could be directly applied on next-generation whole exome or whole genome sequences. Paper I forms a bridge between these two technologies, as it compares the genomic scars extracted from matched TCGA whole exome sequences and single nucleotide polymorphism (SNP) arrays. Paper II and III are the first to report the presence of clear genomic signs of HR-deficiency in two different tumor types. Paper II investigates whether breast cancer brain metastases (BCBM) have differing HR phenotypes than their primary tumors, and concludes that the HR-deficiency-associated genomic scars are significantly higher in BCBM tumors than in their primary counterparts. Paper III addresses HR-deficiency in non-small-cell lung cancers (NSCLC), and it reports HRD-related markers in lung squamous cell carcinomas and adenocarcinomas. The primary goal of these papers is to draw the attention of future clinical trials to the existence of likely PARP-inhibitor sensitive subgroups of patients within the investigated tumor types.Paper IV is highly technical with important clinical utility, and it is also connected to the extraction of HRD-related biomarkers. It describes a machine learning application that can be used for the filtration of formalin-induced sequencing artifacts from paired-end next-generation sequencing data. Although formalin-fixed paraffin-embedded tissue processing is a highly efficient way of cancer specimen storage, without an artifact filtration step, neither the detection of individual mutations nor the extraction of DNA aberration-based biomarkers is reliable enough to make conclusions based on them.

Published
2019

33. Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

Author

Sztupinszki, Zsofia, primary, Diossy, Miklos, additional, Krzystanek, Marcin, additional, Borcsok, Judit, additional, Pomerantz, Mark, additional, Tisza, Viktoria, additional, Spisak, Sandor, additional, Rusz, Orsolya, additional, Csabai, István, additional, Freedman, Matthew, additional, and Szallasi, Zoltan, additional

Published
2019
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34. A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures

Author

Diossy, Miklos, primary, Sztupinszki, Zsofia, additional, Borcsok, Judit, additional, Krzystanek, Marcin, additional, Tisza, Viktoria, additional, Spisak, Sandor, additional, Rusz, Orsolya, additional, Timar, Jozsef, additional, Csabai, István, additional, Moldvay, Judit, additional, Pedersen, Anders Gorm, additional, Szuts, David, additional, and Szallasi, Zoltan, additional

Published
2019
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36. Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression without inducing homologous recombination deficiency.

Author

Szallasi Z, Diossy M, Tisza V, Li H, Sahgal P, Zhou J, Sztupinszki Z, Young D, Nuosome D, Kuo C, Jiang J, Chen Y, Ebner R, Sesterhenn I, Moncur J, Chesnut G, Petrovics G, T Klus G, Valcz G, Nuzzo P, Ribli D, Börcsök J, Prósz A, Krzystanek M, Ried T, Szüts D, Rizwan K, Kaochar S, Pathania S, D'Andrea A, Csabai I, Srivastava S, Freedman M, Dobi A, and Spisak S

Abstract

We analyzed genomic data derived from the prostate cancer of African and European American men in order to identify differences that may contribute to racial disparity of outcome and that could also define novel therapeutic strategies. In addition to analyzing patient derived next generation sequencing data, we performed FISH based confirmatory studies of Chromodomain helicase DNA-binding protein 1 ( CHD1 ) loss on prostate cancer tissue microarrays. We created CRISPR edited, CHD1 deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. We found that subclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of African American men than in men of European ancestry and it associates with rapid disease progression. We further showed that CHD1 deletion is not associated with homologous recombination deficiency associated mutational signatures in prostate cancer. In prostate cancer cell line models CHD1 deletion did not induce HR deficiency as detected by RAD51 foci formation assay or mutational signatures, which was consistent with the moderate increase of olaparib sensitivity. CHD1 deficient prostate cancer cells, however, showed higher sensitivity to talazoparib. CHD1 loss may contribute to worse outcome of prostate cancer in African American men. A deeper understanding of the interaction between CHD1 loss and PARP inhibitor sensitivity will be needed to determine the optimal use of targeted agents such as talazoparib in the context of castration resistant prostate cancer.

Published
2024
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37. Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer.

Author

Börcsök J, Sztupinszki Z, Bekele R, Gao SP, Diossy M, Samant AS, Dillon KM, Tisza V, Spisák S, Rusz O, Csabai I, Pappot H, Frazier ZJ, Konieczkowski DJ, Liu D, Vasani N, Rodrigues JA, Solit DB, Hoffman-Censits JH, Plimack ER, Rosenberg JE, Lazaro JB, Taplin ME, Iyer G, Brunak S, Lozsa R, Van Allen EM, Szüts D, Mouw KW, and Szallasi Z

Subjects
Cisplatin, DNA Repair genetics, Humans, Xeroderma Pigmentosum Group D Protein, Antineoplastic Agents pharmacology, Sesquiterpenes, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms genetics
Abstract

Purpose: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2 , which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2 -mutant cases., Experimental Design: We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity., Results: We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo , including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models., Conclusions: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven. See related commentary by Jiang and Greenberg, p. 1833 ., (©2020 American Association for Cancer Research.)

Published
2021
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