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28 results on '"Kappagantula, Rajya"'

1. Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy

Author

Walmsley, Charlotte S., Jonsson, Philip, Cheng, Michael L., McBride, Sean, Kaeser, Christopher, Vargas, Herbert Alberto, Laudone, Vincent, Taylor, Barry S., Kappagantula, Rajya, Baez, Priscilla, Richards, Allison L., Noronha, Anne Marie, Perera, Dilmi, Berger, Michael, Solit, David B., Iacobuzio-Donahue, Christine A., Scher, Howard I., Donoghue, Mark T. A., Abida, Wassim, and Schram, Alison M.

Published
2024
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2. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer

Author

Łuksza, Marta, Sethna, Zachary M., Rojas, Luis A., Lihm, Jayon, Bravi, Barbara, Elhanati, Yuval, Soares, Kevin, Amisaki, Masataka, Dobrin, Anton, Hoyos, David, Guasp, Pablo, Zebboudj, Abderezak, Yu, Rebecca, Chandra, Adrienne Kaya, Waters, Theresa, Odgerel, Zagaa, Leung, Joanne, Kappagantula, Rajya, Makohon-Moore, Alvin, Johns, Amber, Gill, Anthony, Gigoux, Mathieu, Wolchok, Jedd, Merghoub, Taha, Sadelain, Michel, Patterson, Erin, Monasson, Remi, Mora, Thierry, Walczak, Aleksandra M., Cocco, Simona, Iacobuzio-Donahue, Christine, Greenbaum, Benjamin D., and Balachandran, Vinod P.

Published
2022
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4. Germ cell tumors and associated hematologic malignancies evolve from a common shared precursor

Author

Taylor, Justin, Donoghue, Mark T.A., Ho, Caleb, Petrova-Drus, Kseniya, Al-Ahmadie, Hikmat A., Funt, Samuel A., Zhang, Yanming, Aypar, Umut, Rao, Pavitra, Chavan, Shweta S., Haddadin, Michael, Tamari, Roni, Giralt, Sergio, Tallman, Martin S., Rampal, Raajit K., Baez, Priscilla, Kappagantula, Rajya, Kosuri, Satyajit, Dogan, Ahmet, Tickoo, Satish K., Reuter, Victor E., Bosl, George J., Iacobuzio-Donahue, Christine A., Solit, David B., Taylor, Barry S., Feldman, Darren R., and Abdel-Wahab, Omar

Subjects
Genotypes -- Identification and classification -- Health aspects, Germinoma -- Genetic aspects -- Development and progression -- Care and treatment, Gene mutation -- Health aspects, Gene expression -- Health aspects, Health care industry
Abstract

Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggest a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date, however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals have not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of 15 patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced p53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor that gives rise to the parallel evolution of GCTs and blood cancers in these patients., Introduction Germ cell tumors (GCTs) are a model of curable cancer, as most patients with metastatic GCTs are successfully treated with cisplatin-based chemotherapy (1). However, up to 30% of patients [...]

Published
2020
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5. Author Correction: Accelerated single cell seeding in relapsed multiple myeloma

Author

Landau, Heather J., Yellapantula, Venkata, Diamond, Benjamin T., Rustad, Even H., Maclachlan, Kylee H., Gundem, Gunes, Medina-Martinez, Juan, Ossa, Juan Arango, Levine, Max F., Zhou, Yangyu, Kappagantula, Rajya, Baez, Priscilla, Attiyeh, Marc, Makohon-Moore, Alvin, Zhang, Lance, Boyle, Eileen M., Ashby, Cody, Blaney, Patrick, Patel, Minal, Zhang, Yanming, Dogan, Ahmet, Chung, David J., Giralt, Sergio, Lahoud, Oscar B., Peled, Jonathan U., Scordo, Michael, Shah, Gunjan, Hassoun, Hani, Korde, Neha S., Lesokhin, Alexander M., Lu, Sydney, Mailankody, Sham, Shah, Urvi, Smith, Eric, Hultcrantz, Malin L., Ulaner, Gary A., van Rhee, Frits, Morgan, Gareth J., Landgren, Ola, Papaemmanuil, Elli, Iacobuzio-Donahue, Christine, and Maura, Francesco

Published
2021
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7. CT radiomics associations with genotype and stromal content in pancreatic ductal adenocarcinoma

Author

Attiyeh, Marc A., Chakraborty, Jayasree, McIntyre, Caitlin A., Kappagantula, Rajya, Chou, Yuting, Askan, Gokce, Seier, Kenneth, Gonen, Mithat, Basturk, Olca, Balachandran, Vinod P., Kingham, T. Peter, D’Angelica, Michael I., Drebin, Jeffrey A., Jarnagin, William R., Allen, Peter J., Iacobuzio-Donahue, Christine A., Simpson, Amber L., and Do, Richard K.

Published
2019
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8. Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse

Author

DeWolf, Susan, primary, Elhanati, Yuval, additional, Nichols, Katherine, additional, Waters, Nicholas R., additional, Nguyen, Chi L., additional, Slingerland, John B., additional, Rodriguez, Natasia, additional, Lyudovyk, Olga, additional, Giardina, Paul A., additional, Kousa, Anastasia I., additional, Andrlová, Hana, additional, Ceglia, Nick, additional, Fei, Teng, additional, Kappagantula, Rajya, additional, Li, Yanyun, additional, Aleynick, Nathan, additional, Baez, Priscilla, additional, Murali, Rajmohan, additional, Hayashi, Akimasa, additional, Lee, Nicole, additional, Gipson, Brianna, additional, Rangesa, Madhumitha, additional, Katsamakis, Zoe, additional, Dai, Anqi, additional, Blouin, Amanda G., additional, Arcila, Maria, additional, Masilionis, Ignas, additional, Chaligne, Ronan, additional, Ponce, Doris M., additional, Landau, Heather J., additional, Politikos, Ioannis, additional, Tamari, Roni, additional, Hanash, Alan M., additional, Jenq, Robert R., additional, Giralt, Sergio A., additional, Markey, Kate A., additional, Zhang, Yanming, additional, Perales, Miguel-Angel, additional, Socci, Nicholas D., additional, Greenbaum, Benjamin D., additional, Iacobuzio-Donahue, Christine A., additional, Hollmann, Travis J., additional, van den Brink, Marcel R. M., additional, and Peled, Jonathan U., additional

Published
2023
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9. Accelerated single cell seeding in relapsed multiple myeloma

Author

Landau, Heather J., Yellapantula, Venkata, Diamond, Benjamin T., Rustad, Even H., Maclachlan, Kylee H., Gundem, Gunes, Medina-Martinez, Juan, Ossa, Juan Arango, Levine, Max F., Zhou, Yangyu, Kappagantula, Rajya, Baez, Priscilla, Attiyeh, Marc, Makohon-Moore, Alvin, Zhang, Lance, Boyle, Eileen M., Ashby, Cody, Blaney, Patrick, Patel, Minal, Zhang, Yanming, Dogan, Ahmet, Chung, David J., Giralt, Sergio, Lahoud, Oscar B., Peled, Jonathan U., Scordo, Michael, Shah, Gunjan, Hassoun, Hani, Korde, Neha S., Lesokhin, Alexander M., Lu, Sydney, Mailankody, Sham, Shah, Urvi, Smith, Eric, Hultcrantz, Malin L., Ulaner, Gary A., van Rhee, Frits, Morgan, Gareth J., Landgren, Ola, Papaemmanuil, Elli, Iacobuzio-Donahue, Christine, and Maura, Francesco

Published
2020
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11. Supplementary Data from The Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Sakamoto, Hitomi, primary, Attiyeh, Marc A., primary, Gerold, Jeffrey M., primary, Makohon-Moore, Alvin P., primary, Hayashi, Akimasa, primary, Hong, Jungeui, primary, Kappagantula, Rajya, primary, Zhang, Lance, primary, Melchor, Jerry P., primary, Reiter, Johannes G., primary, Heyde, Alexander, primary, Bielski, Craig M., primary, Penson, Alexander V., primary, Gönen, Mithat, primary, Chakravarty, Debyani, primary, O'Reilly, Eileen M., primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Nowak, Martin A., primary, Socci, Nicholas D., primary, Taylor, Barry S., primary, and Iacobuzio-Donahue, Christine A., primary

Published
2023
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12. Data from The Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Sakamoto, Hitomi, primary, Attiyeh, Marc A., primary, Gerold, Jeffrey M., primary, Makohon-Moore, Alvin P., primary, Hayashi, Akimasa, primary, Hong, Jungeui, primary, Kappagantula, Rajya, primary, Zhang, Lance, primary, Melchor, Jerry P., primary, Reiter, Johannes G., primary, Heyde, Alexander, primary, Bielski, Craig M., primary, Penson, Alexander V., primary, Gönen, Mithat, primary, Chakravarty, Debyani, primary, O'Reilly, Eileen M., primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Nowak, Martin A., primary, Socci, Nicholas D., primary, Taylor, Barry S., primary, and Iacobuzio-Donahue, Christine A., primary

Published
2023
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13. Tables S1-S8 from The Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Sakamoto, Hitomi, primary, Attiyeh, Marc A., primary, Gerold, Jeffrey M., primary, Makohon-Moore, Alvin P., primary, Hayashi, Akimasa, primary, Hong, Jungeui, primary, Kappagantula, Rajya, primary, Zhang, Lance, primary, Melchor, Jerry P., primary, Reiter, Johannes G., primary, Heyde, Alexander, primary, Bielski, Craig M., primary, Penson, Alexander V., primary, Gönen, Mithat, primary, Chakravarty, Debyani, primary, O'Reilly, Eileen M., primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Nowak, Martin A., primary, Socci, Nicholas D., primary, Taylor, Barry S., primary, and Iacobuzio-Donahue, Christine A., primary

Published
2023
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14. Data from The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas

Author

Makohon-Moore, Alvin P., primary, Lipson, Evan J., primary, Hooper, Jody E., primary, Zucker, Amanda, primary, Hong, Jungeui, primary, Bielski, Craig M., primary, Hayashi, Akimasa, primary, Tokheim, Collin, primary, Baez, Priscilla, primary, Kappagantula, Rajya, primary, Kohutek, Zachary, primary, Makarov, Vladimir, primary, Riaz, Nadeem, primary, Postow, Michael A., primary, Chapman, Paul B., primary, Karchin, Rachel, primary, Socci, Nicholas D., primary, Solit, David B., primary, Chan, Timothy A., primary, Taylor, Barry S., primary, Topalian, Suzanne L., primary, and Iacobuzio-Donahue, Christine A., primary

Published
2023
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15. Tables S1-S8 from The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas

Author

Makohon-Moore, Alvin P., primary, Lipson, Evan J., primary, Hooper, Jody E., primary, Zucker, Amanda, primary, Hong, Jungeui, primary, Bielski, Craig M., primary, Hayashi, Akimasa, primary, Tokheim, Collin, primary, Baez, Priscilla, primary, Kappagantula, Rajya, primary, Kohutek, Zachary, primary, Makarov, Vladimir, primary, Riaz, Nadeem, primary, Postow, Michael A., primary, Chapman, Paul B., primary, Karchin, Rachel, primary, Socci, Nicholas D., primary, Solit, David B., primary, Chan, Timothy A., primary, Taylor, Barry S., primary, Topalian, Suzanne L., primary, and Iacobuzio-Donahue, Christine A., primary

Published
2023
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16. Figure S4 from The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas

Author

Makohon-Moore, Alvin P., primary, Lipson, Evan J., primary, Hooper, Jody E., primary, Zucker, Amanda, primary, Hong, Jungeui, primary, Bielski, Craig M., primary, Hayashi, Akimasa, primary, Tokheim, Collin, primary, Baez, Priscilla, primary, Kappagantula, Rajya, primary, Kohutek, Zachary, primary, Makarov, Vladimir, primary, Riaz, Nadeem, primary, Postow, Michael A., primary, Chapman, Paul B., primary, Karchin, Rachel, primary, Socci, Nicholas D., primary, Solit, David B., primary, Chan, Timothy A., primary, Taylor, Barry S., primary, Topalian, Suzanne L., primary, and Iacobuzio-Donahue, Christine A., primary

Published
2023
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17. Tissue-Specific Landscape of the Human T Cell Repertoire in Graft-Versus-Host Disease

Author

DeWolf, Susan, primary, Nichols, Katherine, additional, Elhanati, Yuval, additional, Nguyen, Chi L., additional, Waters, Nicholas R., additional, Rodriguez, Natasia, additional, Giardina, Paul A., additional, Slingerland, John B., additional, Andrlová, Hana, additional, Kappagantula, Rajya, additional, Li, Yanyun, additional, Baez, Priscilla, additional, Murali, Rajmohan, additional, Hayashi, Akimasa, additional, Lee, Nicole, additional, Dai, Anqi, additional, Kousa, Anastasia I., additional, Blouin, Amanda G., additional, Ponce, Doris M., additional, Landau, Heather J., additional, Politikos, Ioannis, additional, Tamari, Roni, additional, Hanash, Alan M., additional, Jenq, Robert R., additional, Giralt, Sergio A., additional, Markey, Kate A., additional, Zhang, Yanming, additional, Perales, Miguel-Angel, additional, Socci, Nicholas D., additional, Greenbaum, Benjamin D., additional, Iacobuzio-Donahue, Christine, additional, Hollmann, Travis J., additional, van den Brink, Marcel R.M., additional, and Peled, Jonathan U., additional

Published
2022
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18. Abstract PR-003: High quality neoantigens are immunoedited in long-term pancreatic cancer survivors

Author

Rojas, Luis A., primary, Łuksza, Marta, additional, Sethna, Zachary M., additional, Soares, Kevin, additional, Leung, Joanne, additional, Lihm, Jayon, additional, Hoyos, David, additional, Dobrin, Anton, additional, Kappagantula, Rajya, additional, Makohon-Moore, Alvin, additional, Johns, Amber, additional, Gill, Anthony, additional, Amisaki, Masataka, additional, Guasp, Pablo, additional, Zebboudj, Abderezak, additional, Yu, Rebecca, additional, Chandra, Adrienne Kaya, additional, Odgerel, Zagaa, additional, Sadelain, Michel, additional, Patterson, Erin, additional, Iacobuzio-Donahue, Christine, additional, Greenbaum, Benjamin D., additional, and Balachandran, Vinod P., additional

Published
2021
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19. 824 High quality neoantigens are immunoedited in long-term pancreatic cancer survivors

Author

Sethna, Zachary, primary, Luksza, Marta, additional, Rojas, Luis, additional, Soares, Kevin, additional, Leung, Joanne, additional, Lihm, Jayon, additional, Hoyos, David, additional, Dobrin, Anton, additional, Kappagantula, Rajya, additional, Makohon-Moore, Alvin, additional, Johns, Amber, additional, Gill, Antony, additional, Amisaki, Masataka, additional, Guasp, Pablo, additional, Zebboudj, Abderezak, additional, Yu, Rebecca, additional, Chandra, Adrienne Kaya, additional, Odgerel, Zagaa, additional, Sadelain, Michel, additional, Patterson, Erin, additional, Iacobuzio-Donahue, Christine, additional, Greenbaum, Benjamin, additional, and Balachandran, Vinod, additional

Published
2021
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20. Abstract LB005: High quality neoantigens are immunoedited in long term survivors of pancreatic cancer

Author

Luksza, Marta, primary, Sethna, Zachary, additional, Rojas, Luis, additional, Soares, Kevin, additional, Elhanati, Yuval, additional, Lihm, Jayon, additional, Hoyos, David, additional, Kappagantula, Rajya, additional, Moore, Alvin M., additional, Patterson, Erin, additional, Iacobuzio-Donahue, Christine, additional, Greenbaum, Benjamin, additional, and Balachandran, Vinod P., additional

Published
2021
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21. The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas

Author

Makohon-Moore, Alvin P., primary, Lipson, Evan J., additional, Hooper, Jody E., additional, Zucker, Amanda, additional, Hong, Jungeui, additional, Bielski, Craig M., additional, Hayashi, Akimasa, additional, Tokheim, Collin, additional, Baez, Priscilla, additional, Kappagantula, Rajya, additional, Kohutek, Zachary, additional, Makarov, Vladimir, additional, Riaz, Nadeem, additional, Postow, Michael A., additional, Chapman, Paul B., additional, Karchin, Rachel, additional, Socci, Nicholas D., additional, Solit, David B., additional, Chan, Timothy A., additional, Taylor, Barry S., additional, Topalian, Suzanne L., additional, and Iacobuzio-Donahue, Christine A., additional

Published
2021
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22. Evolutionary Dynamics of Non-Coding Regions in Pancreatic Ductal Adenocarcinoma

Author

Hayashi, Akimasa, primary, Ho, Yu-jui, additional, Makohon-Moore, Alvin P., additional, Zucker, Amanda, additional, Hong, Jungeui, additional, Reiter, Johannes G., additional, Huang, Jinlong, additional, Zhang, Lance, additional, Attiyeh, Marc A., additional, Baez, Priscilla, additional, Kappagantula, Rajya, additional, Melchor, Jerry P., additional, O’Reilly, Eileen M., additional, Socci, Nicholas D., additional, Oki, Shinya, additional, Lowe, Scott W., additional, and Iacobuzio-Donahue, Christine A., additional

Published
2020
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23. The Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Sakamoto, Hitomi, primary, Attiyeh, Marc A., additional, Gerold, Jeffrey M., additional, Makohon-Moore, Alvin P., additional, Hayashi, Akimasa, additional, Hong, Jungeui, additional, Kappagantula, Rajya, additional, Zhang, Lance, additional, Melchor, Jerry P., additional, Reiter, Johannes G., additional, Heyde, Alexander, additional, Bielski, Craig M., additional, Penson, Alexander V., additional, Gönen, Mithat, additional, Chakravarty, Debyani, additional, O'Reilly, Eileen M., additional, Wood, Laura D., additional, Hruban, Ralph H., additional, Nowak, Martin A., additional, Socci, Nicholas D., additional, Taylor, Barry S., additional, and Iacobuzio-Donahue, Christine A., additional

Published
2020
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24. Accelerated single cell seeding in relapsed multiple myeloma

Author

Landau, Heather, primary, Yellapantula, Venkata, additional, Diamond, Benjamin T., additional, Rustad, Even H., additional, Maclachlan, Kylee H., additional, Gundem, Gunes, additional, Medina-Martinez, Juan, additional, Arango Ossa, Juan, additional, Levine, Max, additional, Zhou, Yangyu, additional, Kappagantula, Rajya, additional, Baez, Priscilla, additional, Attiye, Marc, additional, Makohon-Moore, Alvin, additional, Zhang, Lance, additional, Boyle, Eileen M, additional, Ashby, Cody, additional, Blaney, Patrick, additional, Patel, Minal, additional, Zhang, Yanming, additional, Dogan, Ahmet, additional, Chung, David, additional, Giralt, Sergio, additional, Lahoud, Oscar B., additional, Peled, Jonathan U., additional, Scordo, Michael, additional, Shah, Gunjan, additional, Hassoun, Hani, additional, Korde, Neha S., additional, Lesokhin, Alexander M., additional, Lu, Sydney, additional, Mailankody, Sham, additional, Shah, Urvi, additional, Smith, Eric, additional, Hultcrantz, Malin L., additional, Ulaner, Gary A., additional, van Rhee, Frits, additional, Morgan, Gareth, additional, Ola Landgren, C., additional, Papaemmanuil, Elli, additional, Iacobuzio-Donahue, Christine, additional, and Maura, Francesco, additional

Published
2020
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25. A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma

Author

Hayashi, Akimasa, primary, Fan, Jun, additional, Chen, Ruoyao, additional, Ho, Yu-jui, additional, Makohon-Moore, Alvin P., additional, Lecomte, Nicolas, additional, Zhong, Yi, additional, Hong, Jungeui, additional, Huang, Jinlong, additional, Sakamoto, Hitomi, additional, Attiyeh, Marc A., additional, Kohutek, Zachary A., additional, Zhang, Lance, additional, Boumiza, Aida, additional, Kappagantula, Rajya, additional, Baez, Priscilla, additional, Bai, Jessica, additional, Lisi, Marta, additional, Chadalavada, Kalyani, additional, Melchor, Jerry P., additional, Wong, Winston, additional, Nanjangud, Gouri J., additional, Basturk, Olca, additional, O’Reilly, Eileen M., additional, Klimstra, David S., additional, Hruban, Ralph H., additional, Wood, Laura D., additional, Overholtzer, Michael, additional, and Iacobuzio-Donahue, Christine A., additional

Published
2020
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26. Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Sakamoto, Hitomi, primary, Attiyeh, Marc A., additional, Gerold, Jeffrey M., additional, Makohon-Moore, Alvin P., additional, Hayashi, Akimasa, additional, Hong, Jungeui, additional, Kappagantula, Rajya, additional, Zhang, Lance, additional, Melchor, Jerry, additional, Reiter, Johannes G., additional, Heyde, Alexander, additional, Bielski, Craig M., additional, Penson, Alexander, additional, Chakravarty, Debyani, additional, O’Reilly, Eileen M., additional, Wood, Laura D., additional, Hruban, Ralph H., additional, Nowak, Martin A., additional, Socci, Nicholas D., additional, Taylor, Barry S., additional, and Iacobuzio-Donahue, Christine A., additional

Published
2019
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27. The Genetic Basis of Transcriptional and Spatial Heterogeneity of Squamous Features in Pancreatic Ductal Adenocarcinoma

Author

Hayashi, Akimasa, primary, Fan, Jun, additional, Chen, Ruoyao, additional, Ho, Yu-jui, additional, Makohon-Moore, Alvin P., additional, Zhong, Yi, additional, Hong, Jungeui, additional, Sakamoto, Hitomi, additional, Attiyeh, Marc A., additional, Kohutek, Zachary A., additional, Zhang, Lance, additional, Huang, Jinlong, additional, Boumiza, Aida, additional, Kappagantula, Rajya, additional, Baez, Priscilla, additional, Wood, Laura D., additional, Hruban, Ralph H., additional, Marta, Lisi, additional, Chadalavada, Kalyani, additional, Nanjangud, Gouri J., additional, Basturk, Olca, additional, Klimstra, David S., additional, Overholtzer, Michael, additional, and Iacobuzio-Donahue, Christine A., additional

Published
2019
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28. A microglia clonal inflammatory disorder in Alzheimer's Disease.

Author

Vicario R, Fragkogianni S, Weber L, Lazarov T, Hu Y, Hayashi SY, Craddock BP, Socci ND, Alberdi A, Baako A, Ay O, Ogishi M, Lopez-Rodrigo E, Kappagantula R, Viale A, Iacobuzio-Donahue CA, Zhou T, Ransohoff RM, Chesworth R, Abdel-Wahab O, Boisson B, Elemento O, Casanova JL, Miller WT, and Geissmann F

Abstract

Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimer's Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients., Competing Interests: Competing interests. FG has been a paid consultant (no equity) to Third Rock Ventures from 2018 to 2020. Sequencing costs and analysis in this study were covered in part by a SRA between Third Rock venture and MSKCC. This work led to patents PCT/US2022/037893/WO2023004054A1 ‘Methods and compositions for the treatment of alzheimer’s disease’ by MSKCC and PCT/US2018/047964 ‘Kinase mutation-associated neurodegenerative disorders by MSKCC’.

Published
2024
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