569 results on '"Marra A"'
Search Results
2. Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma
- Author
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Thomas, Nicole, Dreval, Kostiantyn, Gerhard, Daniela S., Hilton, Laura K., Abramson, Jeremy S., Ambinder, Richard F., Barta, Stefan, Bartlett, Nancy L., Bethony, Jeffrey, Bhatia, Kishor, Bowen, Jay, Bryan, Anthony C., Cesarman, Ethel, Casper, Corey, Chadburn, Amy, Cruz, Manuela, Dittmer, Dirk P., Dyer, Maureen A., Farinha, Pedro, Gastier-Foster, Julie M., Gerrie, Alina S., Grande, Bruno M., Greiner, Timothy, Griner, Nicholas B., Gross, Thomas G., Harris, Nancy L., Irvin, John D., Jaffe, Elaine S., Henry, David, Huppi, Rebecca, Leal, Fabio E., Lee, Michael S., Martin, Jean Paul, Martin, Marie-Reine, Mbulaiteye, Sam M., Mitsuyasu, Ronald, Morris, Vivian, Mullighan, Charles G., Mungall, Andrew J., Mungall, Karen, Mutyaba, Innocent, Nokta, Mostafa, Namirembe, Constance, Noy, Ariela, Ogwang, Martin D., Omoding, Abraham, Orem, Jackson, Ott, German, Petrello, Hilary, Pittaluga, Stefania, Phelan, James D., Ramos, Juan Carlos, Ratner, Lee, Reynolds, Steven J., Rubinstein, Paul G., Sissolak, Gerhard, Slack, Graham, Soudi, Shaghayegh, Swerdlow, Steven H., Traverse-Glehen, Alexandra, Wilson, Wyndham H., Wong, Jasper, Yarchoan, Robert, ZenKlusen, Jean C., Marra, Marco A., Staudt, Louis M., Scott, David W., and Morin, Ryan D.
- Published
- 2023
- Full Text
- View/download PDF
3. Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma
- Author
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Mottok, Anja, Hung, Stacy S., Chavez, Elizabeth A., Woolcock, Bruce, Telenius, Adèle, Chong, Lauren C., Meissner, Barbara, Nakamura, Hisae, Rushton, Christopher, Viganò, Elena, Sarkozy, Clementine, Gascoyne, Randy D., Connors, Joseph M., Ben-Neriah, Susana, Mungall, Andrew, Marra, Marco A., Siebert, Reiner, Scott, David W., Savage, Kerry J., and Steidl, Christian
- Published
- 2019
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4. Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin–specific clinical impact
- Author
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Ennishi, Daisuke, Mottok, Anja, Ben-Neriah, Susana, Shulha, Hennady P., Farinha, Pedro, Chan, Fong Chun, Meissner, Barbara, Boyle, Merrill, Hother, Christoffer, Kridel, Robert, Lai, Daniel, Saberi, Saeed, Bashashati, Ali, Shah, Sohrab P., Morin, Ryan D., Marra, Marco A., Savage, Kerry J., Sehn, Laurie H., Steidl, Christian, Connors, Joseph M., Gascoyne, Randy D., and Scott, David W.
- Published
- 2017
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- View/download PDF
5. Towards a Unified Genetic Classification System for Diffuse Large B-Cell Lymphoma (DLBCL)
- Author
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Kostiantyn Dreval, Laura K Hilton, Krysta M. Coyle, Jasper Wong, Merrill Boyle, Brett Collinge, Manuela Cruz, Barbara Meissner, Christopher K Rushton, Marco A. Marra, David W. Scott, Christian Steidl, and Ryan D. Morin
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
6. DNA Methylation-Based Burkitt Lymphoma Epitypes Have Distinct Molecular and Clinical Features
- Author
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Nicole Thomas, Kostiantyn Dreval, Daniela S. Gerhard, Laura K Hilton, Jeremy S. Abramson, Nancy L. Bartlett, Jeffrey Bethony, Jay Bowen, Anthony Bryan, Corey Casper, Maureen Dyer, Manel Esteller, Carlos Garcia-Prieto, Julie M Gastier-Foster, Alina S. Gerrie, Bruno M. Grande, Timothy C. Greiner, Nicholas B. Griner, Thomas G. Gross, Nancy Lee Harris, John D. Irvin, Elaine S. Jaffe, Fabio Leal, Jean Paul Martin, Marie-Reine Martin, Sam M. Mbulaiteye, Charles G. Mullighan, Andrew J. Mungall, Karen Mungall, Constance Namirembe, Ariela Noy, Martin D Ogwang, Jackson Orem, German Ott, Hilary Petrello, Steven J Reynolds, Steven H. Swerdlow, Alexandra Traverse-Glehen, Wyndham H. Wilson, Marco A. Marra, Louis M. Staudt, David W. Scott, and Ryan D. Morin
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. Relapse Timing Is Associated with Distinct Evolutionary Dynamics and Response to Salvage Therapy in DLBCL
- Author
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Laura K Hilton, Henry S. Ngu, Brett Collinge, Kostiantyn Dreval, Susana Ben-Neriah, Christopher K Rushton, Jasper Wong, Manuela Cruz, Andrew Roth, Merrill Boyle, Barbara Meissner, Graham W. Slack, Pedro Farinha, Jeffrey W. Craig, Alina S. Gerrie, Ciara L. Freeman, Diego Villa, Kerry J. Savage, Laurie H. Sehn, Marco A. Marra, Aly Karsan, Christian Steidl, Ryan D. Morin, and David W. Scott
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
8. Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas
- Author
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Chong, Lauren C., Twa, David D.W., Mottok, Anja, Ben-Neriah, Susana, Woolcock, Bruce W., Zhao, Yongjun, Savage, Kerry J., Marra, Marco A., Scott, David W., Gascoyne, Randy D., Morin, Ryan D., Mungall, Andrew J., and Steidl, Christian
- Published
- 2016
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9. Clinical impact of molecular features in diffuse large B-cell lymphoma and follicular lymphoma
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Pon, Julia R. and Marra, Marco A.
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- 2016
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10. Cell of origin of transformed follicular lymphoma
- Author
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Kridel, Robert, Mottok, Anja, Farinha, Pedro, Ben-Neriah, Susana, Ennishi, Daisuke, Zheng, Yvonne, Chavez, Elizabeth A., Shulha, Hennady P., Tan, King, Chan, Fong Chun, Boyle, Merrill, Meissner, Barbara, Telenius, Adele, Sehn, Laurie H., Marra, Marco A., Shah, Sohrab P., Steidl, Christian, Connors, Joseph M., Scott, David W., and Gascoyne, Randy D.
- Published
- 2015
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11. An RCOR1 loss–associated gene expression signature identifies a prognostically significant DLBCL subgroup
- Author
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Chan, Fong Chun, Telenius, Adele, Healy, Shannon, Ben-Neriah, Susana, Mottok, Anja, Lim, Raymond, Drake, Marie, Hu, Sandy, Ding, Jiarui, Ha, Gavin, Scott, David W., Kridel, Robert, Bashashati, Ali, Rogic, Sanja, Johnson, Nathalie, Morin, Ryan D., Rimsza, Lisa M., Sehn, Laurie, Connors, Joseph M., Marra, Marco A., Gascoyne, Randy D., Shah, Sohrab P., and Steidl, Christian
- Published
- 2015
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12. Towards a Unified Genetic Classification System for Diffuse Large B-Cell Lymphoma (DLBCL)
- Author
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Dreval, Kostiantyn, primary, Hilton, Laura K, additional, Coyle, Krysta M., additional, Wong, Jasper, additional, Boyle, Merrill, additional, Collinge, Brett, additional, Cruz, Manuela, additional, Meissner, Barbara, additional, Rushton, Christopher K, additional, Marra, Marco A., additional, Scott, David W., additional, Steidl, Christian, additional, and Morin, Ryan D., additional
- Published
- 2022
- Full Text
- View/download PDF
13. DNA Methylation-Based Burkitt Lymphoma Epitypes Have Distinct Molecular and Clinical Features
- Author
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Thomas, Nicole, primary, Dreval, Kostiantyn, additional, Gerhard, Daniela S., additional, Hilton, Laura K, additional, Abramson, Jeremy S., additional, Bartlett, Nancy L., additional, Bethony, Jeffrey, additional, Bowen, Jay, additional, Bryan, Anthony, additional, Casper, Corey, additional, Dyer, Maureen, additional, Esteller, Manel, additional, Garcia-Prieto, Carlos, additional, Gastier-Foster, Julie M, additional, Gerrie, Alina S., additional, Grande, Bruno M., additional, Greiner, Timothy C., additional, Griner, Nicholas B., additional, Gross, Thomas G., additional, Harris, Nancy Lee, additional, Irvin, John D., additional, Jaffe, Elaine S., additional, Leal, Fabio, additional, Martin, Jean Paul, additional, Martin, Marie-Reine, additional, Mbulaiteye, Sam M., additional, Mullighan, Charles G., additional, Mungall, Andrew J., additional, Mungall, Karen, additional, Namirembe, Constance, additional, Noy, Ariela, additional, Ogwang, Martin D, additional, Orem, Jackson, additional, Ott, German, additional, Petrello, Hilary, additional, Reynolds, Steven J, additional, Swerdlow, Steven H., additional, Traverse-Glehen, Alexandra, additional, Wilson, Wyndham H., additional, Marra, Marco A., additional, Staudt, Louis M., additional, Scott, David W., additional, and Morin, Ryan D., additional
- Published
- 2022
- Full Text
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14. Recurrent Copy Number Alterations Contribute to a Unique Genetic Landscape in Relapsed-Refractory DLBCL
- Author
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Rushton, Christopher K, primary, Rys, Ryan N, additional, Chavez, Elizabeth, additional, Hilton, Laura K, additional, Alcaide, Miguel, additional, Dreval, Kostiantyn, additional, Cheung, Matthew, additional, Cruz, Manuela, additional, Coyle, Krysta M., additional, Meissner, Barbara, additional, Ben-Neriah, Susana, additional, Michaud, Neil R., additional, Daigle, Scott, additional, Davidson, Jordan, additional, Wong, Jasper, additional, Hay, Annette E., additional, Jain, Michael D., additional, Shepherd, Lois E., additional, Marra, Marco A., additional, Kuruvilla, John, additional, Crump, Michael, additional, Mann, Koren Kathleen, additional, Assouline, Sarit, additional, Steidl, Christian, additional, Scott, David W., additional, Johnson, Nathalie A., additional, and Morin, Ryan D., additional
- Published
- 2022
- Full Text
- View/download PDF
15. Tuned IL3-Zetakine Coupled to a CD33 Costimulatory Receptor As a Dual CAR for Safer and Selective Targeting of Acute Myeloid Leukemia
- Author
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Perriello, Vincenzo Maria, primary, Rotiroti, Maria Caterina, additional, Pisani, Ilaria, additional, Galimberti, Stefania, additional, Alberti, Gaia, additional, Pianigiani, Giulia, additional, Ciaurro, Valerio, additional, Marra, Andrea, additional, Sabino, Marcella, additional, Tini, Valentina, additional, Mezzasoma, Federica, additional, Morena, Francesco, additional, Martino, Sabata, additional, Salerno, Domenico, additional, Ashby, Julian François, additional, Wingham, Brittany, additional, Serafini, Marta, additional, Martelli, Maria Paola, additional, Falini, Brunangelo, additional, Biondi, Andrea, additional, and Tettamanti, Sarah, additional
- Published
- 2022
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16. Genome-Wide Methylation and Haplotype-Resolved Aberrant Somatic Hypermutation Patterns in B-Cell Lymphomas
- Author
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Shaalan, Haya, primary, Thomas, Nicole, additional, Boyle, Merrill, additional, Meissner, Barbara, additional, Marra, Marco A., additional, Steidl, Christian, additional, Scott, David W., additional, Hilton, Laura K, additional, and Morin, Ryan D., additional
- Published
- 2022
- Full Text
- View/download PDF
17. Pediatric Age at Hematopoietic Stem Cell Transplant: Associations with Non-Malignant Genetic Disease and Race
- Author
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Higashi, Mitchell K., primary, Kruszka, Paul, additional, Francis, Marra S., additional, Parsons, Kelly K., additional, Oh, William K., additional, and Onel, Kenan, additional
- Published
- 2022
- Full Text
- View/download PDF
18. Relapse Timing Is Associated with Distinct Evolutionary Dynamics and Response to Salvage Therapy in DLBCL
- Author
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Hilton, Laura K, primary, Ngu, Henry S., additional, Collinge, Brett, additional, Dreval, Kostiantyn, additional, Ben-Neriah, Susana, additional, Rushton, Christopher K, additional, Wong, Jasper, additional, Cruz, Manuela, additional, Roth, Andrew, additional, Boyle, Merrill, additional, Meissner, Barbara, additional, Slack, Graham W., additional, Farinha, Pedro, additional, Craig, Jeffrey W., additional, Gerrie, Alina S., additional, Freeman, Ciara L., additional, Villa, Diego, additional, Savage, Kerry J., additional, Sehn, Laurie H., additional, Marra, Marco A., additional, Karsan, Aly, additional, Steidl, Christian, additional, Morin, Ryan D., additional, and Scott, David W., additional
- Published
- 2022
- Full Text
- View/download PDF
19. GENETIC SUBGROUPS INFORM ON PATHOBIOLOGY IN ADULT AND PEDIATRIC BURKITT LYMPHOMA
- Author
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Nicole Thomas, Kostiantyn Dreval, Daniela S. Gerhard, Laura K. Hilton, Jeremy S. Abramson, Richard F. Ambinder, Stefan Barta, Nancy L. Bartlett, Jeffrey Bethony, Kishor Bhatia, Jay Bowen, Anthony C. Bryan, Ethel Cesarman, Corey Casper, Amy Chadburn, Manuela Cruz, Dirk P. Dittmer, Maureen A. Dyer, Pedro Farinha, Julie M. Gastier-Foster, Alina S. Gerrie, Bruno M. Grande, Timothy Greiner, Nicholas B. Griner, Thomas G. Gross, Nancy L. Harris, John D. Irvin, Elaine S. Jaffe, David Henry, Rebecca Huppi, Fabio E. Leal, Michael S. Lee, Jean Paul Martin, Marie-Reine Martin, Sam M. Mbulaiteye, Ronald Mitsuyasu, Vivian Morris, Charles G. Mullighan, Andrew J. Mungall, Karen Mungall, Innocent Mutyaba, Mostafa Nokta, Constance Namirembe, Ariela Noy, Martin D. Ogwang, Abraham Omoding, Jackson Orem, German Ott, Hilary Petrello, Stefania Pittaluga, James D. Phelan, Juan Carlos Ramos, Lee Ratner, Steven J. Reynolds, Paul G. Rubinstein, Gerhard Sissolak, Graham Slack, Shaghayegh Soudi, Steven H. Swerdlow, Alexandra Traverse-Glehen, Wyndham H. Wilson, Jasper Wong, Robert Yarchoan, Jean C. ZenKlusen, Marco A. Marra, Louis M. Staudt, David W. Scott, and Ryan D. Morin
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.
- Published
- 2022
20. Recurrent Copy Number Alterations Contribute to a Unique Genetic Landscape in Relapsed-Refractory DLBCL
- Author
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Christopher K Rushton, Ryan N Rys, Elizabeth Chavez, Laura K Hilton, Miguel Alcaide, Kostiantyn Dreval, Matthew Cheung, Manuela Cruz, Krysta M. Coyle, Barbara Meissner, Susana Ben-Neriah, Neil R. Michaud, Scott Daigle, Jordan Davidson, Jasper Wong, Annette E. Hay, Michael D. Jain, Lois E. Shepherd, Marco A. Marra, John Kuruvilla, Michael Crump, Koren Kathleen Mann, Sarit Assouline, Christian Steidl, David W. Scott, Nathalie A. Johnson, and Ryan D. Morin
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
21. Pediatric Age at Hematopoietic Stem Cell Transplant: Associations with Non-Malignant Genetic Disease and Race
- Author
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Mitchell K. Higashi, Paul Kruszka, Marra S. Francis, Kelly K. Parsons, William K. Oh, and Kenan Onel
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
22. Genome-Wide Methylation and Haplotype-Resolved Aberrant Somatic Hypermutation Patterns in B-Cell Lymphomas
- Author
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Haya Shaalan, Nicole Thomas, Merrill Boyle, Barbara Meissner, Marco A. Marra, Christian Steidl, David W. Scott, Laura K Hilton, and Ryan D. Morin
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
23. Tuned IL3-Zetakine Coupled to a CD33 Costimulatory Receptor As a Dual CAR for Safer and Selective Targeting of Acute Myeloid Leukemia
- Author
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Vincenzo Maria Perriello, Maria Caterina Rotiroti, Ilaria Pisani, Stefania Galimberti, Gaia Alberti, Giulia Pianigiani, Valerio Ciaurro, Andrea Marra, Marcella Sabino, Valentina Tini, Federica Mezzasoma, Francesco Morena, Sabata Martino, Domenico Salerno, Julian François Ashby, Brittany Wingham, Marta Serafini, Maria Paola Martelli, Brunangelo Falini, Andrea Biondi, and Sarah Tettamanti
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
24. Analysis of FOXO1 mutations in diffuse large B-cell lymphoma
- Author
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Trinh, Diane L., Scott, David W., Morin, Ryan D., Mendez-Lago, Maria, An, Jianghong, Jones, Steven J.M., Mungall, Andrew J., Zhao, Yongjun, Schein, Jacqueline, Steidl, Christian, Connors, Joseph M., Gascoyne, Randy D., and Marra, Marco A.
- Published
- 2013
- Full Text
- View/download PDF
25. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma
- Author
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Kridel, Robert, Meissner, Barbara, Rogic, Sanja, Boyle, Merrill, Telenius, Adele, Woolcock, Bruce, Gunawardana, Jay, Jenkins, Catherine E., Cochrane, Chris, Ben-Neriah, Susana, Tan, King, Morin, Ryan D., Opat, Stephen, Sehn, Laurie H., Connors, Joseph M., Marra, Marco A., Weng, Andrew P., Steidl, Christian, and Gascoyne, Randy D.
- Published
- 2012
- Full Text
- View/download PDF
26. Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing
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Sriram Balasubramanian, Quratulain Qureshi, Christopher Rushton, Miguel Alcaide, Nicole Thomas, Krysta M. Coyle, Bruno M. Grande, Prasath Pararajalingam, Barbara Meissner, Joseph M. Connors, Diego Villa, Ryan D. Morin, Constantine S. Tam, Randy D. Gascoyne, David W. Scott, Graham W. Slack, Christian Steidl, Nathalie A. Johnson, Timothy E. Audas, Marco A. Marra, Sarah E. Arthur, Rishu Agarwal, Andrew J. Mungall, Merrill Boyle, Sarah-Jane Dawson, and Georg Lenz
- Subjects
Adult ,Male ,0301 basic medicine ,Genotype ,Immunology ,Lymphoma, Mantle-Cell ,Biology ,medicine.disease_cause ,Biochemistry ,Genome ,Heterogeneous-Nuclear Ribonucleoproteins ,03 medical and health sciences ,Exon ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,Exome ,Exome sequencing ,Aged ,Aged, 80 and over ,Mutation ,Whole Genome Sequencing ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Lymphoma ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Mantle cell lymphoma - Abstract
Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.
- Published
- 2020
27. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation
- Author
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Yap, Damian B., Chu, Justin, Berg, Tobias, Schapira, Matthieu, Cheng, S.-W. Grace, Moradian, Annie, Morin, Ryan D., Mungall, Andrew J., Meissner, Barbara, Boyle, Merrill, Marquez, Victor E., Marra, Marco A., Gascoyne, Randy D., Humphries, R. Keith, Arrowsmith, Cheryl H., Morin, Gregg B., and Aparicio, Samuel A.J.R.
- Published
- 2011
- Full Text
- View/download PDF
28. Genome-wide identification of human microRNAs located in leukemia-associated genomic alterations
- Author
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Starczynowski, Daniel T., Morin, Ryan, McPherson, Andrew, Lam, Jeff, Chari, Raj, Wegrzyn, Joanna, Kuchenbauer, Florian, Hirst, Martin, Tohyama, Kaoru, Humphries, R. Keith, Lam, Wan L., Marra, Marco, and Karsan, Aly
- Published
- 2011
- Full Text
- View/download PDF
29. Constrained FL: A Genetically Distinct Subgroup of Follicular Lymphoma with Low Rates of Somatic Hypermutation and a Reduced Propensity for Histologic Transformation
- Author
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Hilton, Laura K, primary, Dreval, Kostiantyn, additional, Soudi, Shaghayegh, additional, Ben-Neriah, Susana, additional, Cruz, Manuela, additional, Collinge, Brett, additional, Coyle, Krysta M., additional, Grande, Bruno M., additional, Duns, Gerben, additional, Rushton, Christopher K, additional, Boyle, Merrill, additional, Meissner, Barbara, additional, Farinha, Pedro, additional, Slack, Graham W, additional, Mungall, Andrew J., additional, Marra, Marco A., additional, Connors, Joseph M., additional, Steidl, Christian, additional, Scott, David W., additional, and Morin, Ryan D, additional
- Published
- 2021
- Full Text
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30. Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency
- Author
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Zaninoni, Anna, primary, Russo, Roberta, additional, Marra, Roberta, additional, Fermo, Elisa, additional, Andolfo, Immacolata, additional, Marcello, Anna Paola, additional, Consonni, Dario, additional, Rosato, Barbara Eleni, additional, Martone, Stefania, additional, Fattizzo, Bruno, additional, Barcellini, Wilma, additional, Iolascon, Achille, additional, and Bianchi, Paola, additional
- Published
- 2021
- Full Text
- View/download PDF
31. Novel Genetic Subgroups Inform on Shared Pathobiology within Adult and Pediatric Burkitt Lymphoma
- Author
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Thomas, Nicole, primary, Dreval, Kostiantyn, additional, Gerhard, Daniela S., additional, Hilton, Laura K, additional, Abramson, Jeremy S., additional, Bartlett, Nancy L., additional, Bethony, Jeffrey, additional, Bowen, Jay, additional, Bryan, Anthony, additional, Casper, Corey, additional, Cruz, Manuela, additional, Dyer, Maureen, additional, Gastier-Foster, Julie M, additional, Gerrie, Alina S., additional, Grande, Bruno M., additional, Greiner, Timothy C., additional, Griner, Nicholas B., additional, Gross, Thomas G., additional, Harris, Nancy Lee, additional, Irvin, John D., additional, Jaffe, Elaine S., additional, Leal, Fabio, additional, Martin, Jean Paul, additional, Martin, Marie-Reine, additional, Mbulaiteye, Sam M., additional, Mullighan, Charles G., additional, Mungall, Andrew J., additional, Mungall, Karen, additional, Namirembe, Constance, additional, Noy, Ariela, additional, Ogwang, Martin, additional, Orem, Jackson, additional, Ott, German, additional, Petrello, Hilary, additional, Reynolds, Steven, additional, Soudi, Shaghayegh, additional, Swerdlow, Steven H., additional, Traverse-Glehen, Alexandra, additional, Wilson, Wyndham H., additional, Wong, Jasper, additional, Marra, Marco A., additional, Staudt, Louis M., additional, Scott, David W., additional, and Morin, Ryan D, additional
- Published
- 2021
- Full Text
- View/download PDF
32. Complex Structural Variation Associated with Enhancer Hijacking and Loss of Tumor Suppressors in Mantle Cell Lymphoma
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Pararajalingam, Prasath, primary, Hilton, Laura K, additional, Coyle, Krysta M., additional, Dreval, Kostiantyn, additional, Meissner, Barbara, additional, Melnick, Ari, additional, Marra, Marco A., additional, Scott, David W., additional, and Morin, Ryan D, additional
- Published
- 2021
- Full Text
- View/download PDF
33. A Longitudinal Single-Cell Atlas of Treatment Response in Pediatric AML
- Author
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Lambo, Sander, Trinh, Diane L., Ries, Rhonda E, Jin, Dan, Setiadi, Audi, Ng, Michelle, Leblanc, Veronique G., Vercauteren, Suzanne, Meshinchi, Soheil, and Marra, Marco
- Published
- 2023
- Full Text
- View/download PDF
34. Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma
- Author
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Lauren C. Chong, Andrew J. Mungall, Adele Telenius, Reiner Siebert, Christopher Rushton, David Scott, Anja Mottok, Elena Viganò, Susana Ben-Neriah, Stacy Hung, Barbara Meissner, Kerry J. Savage, Bruce Woolcock, Marco A. Marra, Hisae Nakamura, Randy D. Gascoyne, Clémentine Sarkozy, Christian Steidl, Elizabeth A. Chavez, and Joseph M. Connors
- Subjects
Immunology ,Cell Biology ,Hematology ,Gene mutation ,Biology ,medicine.disease ,Biochemistry ,Gray zone lymphoma ,Gene expression profiling ,Cancer research ,medicine ,CIITA ,EP300 ,Diffuse large B-cell lymphoma ,Exome sequencing ,IRF4 - Abstract
Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype–phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.
- Published
- 2019
35. Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential
- Author
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Kent, David G., Copley, Michael R., Benz, Claudia, Wöhrer, Stefan, Dykstra, Brad J., Ma, Elaine, Cheyne, John, Zhao, Yongjun, Bowie, Michelle B., Zhao, Yun, Gasparetto, Maura, Delaney, Allen, Smith, Clayton, Marra, Marco, and Eaves, Connie J.
- Published
- 2009
- Full Text
- View/download PDF
36. Impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC
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Joseph M. Connors, Jeffrey W. Craig, Pedro Farinha, Graham W. Slack, Kerry J. Savage, Brett Collinge, Ryan D. Morin, Diego Villa, Aixiang Jiang, Lauren C. Chong, Tomoko Miyata-Takata, David W. Scott, Elizabeth A. Chavez, Anja Mottok, Daisuke Ennishi, Andrew J. Mungall, Laurie H. Sehn, Randy D. Gascoyne, Susana Ben-Neriah, Barbara Meissner, Marco A. Marra, Ciara L. Freeman, Alina S. Gerrie, Merrill Boyle, and Christian Steidl
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Adult ,Male ,0301 basic medicine ,Immunology ,Context (language use) ,In situ hybridization ,Biology ,Polymorphism, Single Nucleotide ,Biochemistry ,Proto-Oncogene Proteins c-myc ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Gene expression ,medicine ,Humans ,Copy-number variation ,Gene ,Aged ,Aged, 80 and over ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,BCL6 ,Immunohistochemistry ,Lymphoma ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Cancer research ,Female ,Lymphoma, Large B-Cell, Diffuse ,Transcriptome ,030215 immunology - Abstract
When the World Health Organization defined high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) as a clinical category, rearrangements were the only structural variant (SV) incorporated. An "atypical double-hit" category has been proposed, encompassing tumors with concurrent MYC and BCL2 SVs other than cooccurring translocations (ie, copy number variations [CNVs]). Although the identification of a gene expression signature (DHITsig) shared among tumors harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2) has confirmed a common underlying biology, the biological implication of MYC and BCL2 CNVs requires further elucidation. We performed a comprehensive analysis of MYC and BCL2 SVs, as determined by fluorescent in situ hybridization (FISH), in a cohort of 802 de novo tumors with diffuse large B-cell lymphoma morphology. Although BCL2 CNVs were associated with increased expression, MYC CNVs were not. Furthermore, MYC and BCL2 CNVs, in the context of atypical double-hit, did not confer a similar gene expression profile as HGBL-DH/TH-BCL2. Finally, although MYC immunohistochemistry (IHC) has been proposed as a screening tool for FISH testing, 2 mechanisms were observed that uncoupled MYC rearrangement from IHC positivity: (1) low MYC messenger RNA expression; and (2) false-negative IHC staining mediated by a single-nucleotide polymorphism resulting in an asparagine-to-serine substitution at the 11th amino acid residue of MYC (MYC-N11S). Taken together, these results support the current exclusion of MYC and BCL2 CNVs from HGBL-DH/TH and highlight the ability of a molecular-based classification system to identify tumors with shared biology that FISH and IHC fail to fully capture.
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- 2020
37. Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts
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Moretti, Simona, Procopio, Antonio, Lazzarini, Raffaella, Rippo, Maria Rita, Testa, Roberto, Marra, Maurizio, Tamagnone, Luca, and Catalano, Alfonso
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- 2008
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38. Constrained FL: A Genetically Distinct Subgroup of Follicular Lymphoma with Low Rates of Somatic Hypermutation and a Reduced Propensity for Histologic Transformation
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Pedro Farinha, Graham W. Slack, Christopher Rushton, B. M. Grande, Joseph M. Connors, Gerben Duns, Laura K. Hilton, Susana Ben-Neriah, Christian Steidl, Brett Collinge, Krysta M. Coyle, Shaghayegh Soudi, Merrill Boyle, Marco A. Marra, Manuela Cruz, Barbara Meissner, Ryan D. Morin, Kostiantyn Dreval, Andrew J. Mungall, and David W. Scott
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Transformation (genetics) ,Immunology ,Follicular lymphoma ,medicine ,Cancer research ,Somatic hypermutation ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry - Abstract
Introduction: Follicular lymphoma (FL) is an indolent disease that undergoes histological transformation (HT) to aggressive diffuse large B-cell lymphoma (DLBCL) in 8-15% of patients. FLs frequently share genetic features with DLBCL, especially those of the germinal center B-cell-like (GCB) cell-of-origin (COO) and the EZB/C3 genetic subgroup, and approximately 80% of transformed FL (tFL) are classified as GCB. Our current understanding of the genetics of FL and tFL is based on a variety of studies, most of which have sequenced tumors in small case numbers or using targeted approaches such that the potential role of non-coding mutations and aberrant somatic hypermutation (aSHM) in predicting HT have not previously been fully explored. Methods: Whole genome sequencing (WGS) data from 212 FL (including 24 from patients that subsequently underwent HT) and 241 de novo DLBCL were analyzed. Simple somatic mutations (SSMs) were called using an ensemble of somatic variant callers, while structural variants (SVs) were called with Manta and copy number variants (CNVs) with Battenberg and GISTIC. Fluorescence in situ hybridization with break-apart probes (BA-FISH) was used to identify MYC, BCL2, and BCL6 translocations, and with IGH /BCL2 dual-fusion probes (DF-FISH) for a subset of FLs. To compare the genetics of FL and DLBCL, 83 significantly mutated genes (SMGs) were identified with dNdS, MutSigCV, HotMaps, and OncoDriveFML, and non-silent mutations were tabulated for their presence in each genome. For 38 hypermutated regions, we used a region-specific threshold to binarize the data to aSHM/no aSHM. Recurrent missense mutations in FOXO1, MYD88L265P, CREBBP lysine acetyltransferase (KAT) domain, EZH2Y646, MEF2B, and STAT6 were tabulated separately from other mutations in these genes. Using only the FL tumors from patients with no evidence of subsequent transformation and all available de novo DLBCLs, we trained a random forest classifier to separate these two entities using this set of 129 features, including MYC and BCL6 translocations. To validate this classifier, we fit a linear model to the number of FL votes from each discovery case, utilizing the 65 features (including 19 aSHM features) that were adequately sequenced in a validation cohort of 127 tFL. Statistical tests were corrected for multiple comparisons where necessary. Results: This large cohort of FL and DLBCL genomes has enabled the curation of an extensive list of novel and established FL driver genes and the identification of distinguishing genetic features among SMGs and CNVs. Loci that are significantly enriched for mutations in FL vs. DLBCL include the CREBBP KAT domain (OR 11.5, P < 0.0001), RRAGC (OR 9.61, P < 0.001), and ATP6V1B2 (OR 11.17, P < 0.001). Deletions of ARID1A (OR 4.74, P < 0.1), PTEN (OR 3.65, P < 0.01), and TNFRSF14 (OR 3.31, P < 0.01) were among the CNVs significantly enriched in FL. Out of 156 FLs, 24 (15%) were negative for BCL2 translocations by BA-FISH, but 4 (17%) of these had BCL2 translocations detected from WGS data. All 4 of these cryptic events were confirmed using IGH /BCL2 DF-FISH. Using a threshold of 0.7, the linear model separated discovery FL cases into a more DLBCL-like subgroup, termed dFL (n = 107), and a genetically homogeneous subgroup enriched for the FL-associated features, which we describe as constrained FL (cFL, n = 105). This separation is supported by more mutations in dFL vs cFL across several aSHM loci, including the transcription start sites for BCL6, BCL7A, DTX1, and ZFP36L1 (Figure 1), consistent with reduced exposure to the germinal center reaction in cFL. Within the targeted capture validation cohort of tFL, 30 (24%) tumors were classified as cFL and 97 (76%) as dFL. The tFL cohort was significantly depleted for mutations in the CREBBP KAT domain (OR 0.59, P < 0.05), and were significantly less frequently classified as cFL (OR 0.30, P < 0.0001) compared to the discovery FLs. Conclusions: The distinction between cFL and dFL is strongly driven by CREBBP KAT domain mutations and different rates of aSHM genome wide. Given the known early clonal nature of CREBBP mutations in FL and its role in regulating germinal center cycling, we speculate that CREBBP KAT mutations may limit the exposure of FL to the dark zone, reducing the opportunity for aSHM and creating an evolutionary constraint that may limit the opportunity for HT. This classification may serve as a useful biomarker to identify FLs at higher risk of HT. Figure 1 Figure 1. Disclosures Coyle: Allakos, Inc.: Consultancy. Grande: Sage Bionetworks: Current Employment. Slack: Seagen: Consultancy, Honoraria. Steidl: Curis Inc.: Consultancy; Trillium Therapeutics: Research Funding; Epizyme: Research Funding; Bayer: Consultancy; Seattle Genetics: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Research Funding. Scott: Janssen: Consultancy, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; Incyte: Consultancy; Rich/Genentech: Research Funding; Celgene: Consultancy; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. . Morin: Epizyme: Patents & Royalties; Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy.
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- 2021
39. Novel Genetic Subgroups Inform on Shared Pathobiology within Adult and Pediatric Burkitt Lymphoma
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Shaghayegh Soudi, Constance Namirembe, Andrew J. Mungall, Nancy L. Bartlett, Jeffrey M. Bethony, Louis M. Staudt, Julie M. Gastier-Foster, B. M. Grande, Manuela Cruz, Nicholas B. Griner, Timothy C. Greiner, Steven H. Reynolds, Ryan D. Morin, Fabio E. Leal, Kostiantyn Dreval, Wyndham H. Wilson, Anthony C. Bryan, Daniela S. Gerhard, John D. Irvin, German Ott, Thomas G. Gross, Charles G. Mullighan, Karen Mungall, Jeremy S. Abramson, Martin D. Ogwang, David Scott, Elaine S. Jaffe, Ariela Noy, Maureen A. Dyer, Laura K. Hilton, Jay Bowen, S M Mbulaiteye, Nancy L. Harris, J Martín, Marco A. Marra, Alina S. Gerrie, Jackson Orem, Steven H. Swerdlow, Marie-Reine Martin, Hilary Petrello, Nicole Thomas, Corey Casper, Jasper Wong, and Alexandra Traverse-Glehen
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Oncology ,medicine.medical_specialty ,business.industry ,hemic and lymphatic diseases ,Internal medicine ,Immunology ,Medicine ,Cell Biology ,Hematology ,business ,medicine.disease ,Biochemistry ,Lymphoma - Abstract
Introduction: Burkitt lymphoma (BL) accounts for approximately 50% of all pediatric non-Hodgkin lymphomas compared to 1-2% in adults. Adult BL (aBL) remains a poorly understood entity and its relationship to pediatric BL (pBL) and to DLBCL has not been fully elucidated. The variable treatment outcomes between these entities necessitate a more thorough understanding of the genetic and molecular features underlying their biology to enable better prognostication and more effective treatments. We sought to comprehensively determine genetic features shared with DLBCL and those that are unique to BL, to further delineate genetic subgroupings within each entity. Methods: Samples for this study were collected through the Burkitt Lymphoma Genome Sequencing Project (BLGSP). We sequenced the tumor genomes of 139 pBL and 92 aBL, consisting of both EBV-positive (EBV+) and EBV-negative (EBV-) BLs, and compared these to the genomes of 252 DLBCL patients. All cases were analyzed for simple somatic mutations (SSM), recurrent copy number variations (CNV), structural variations (SV), aberrant somatic hypermutation (aSHM), and SSM hotspots. Mutations were used as features for the identification of genetic subgroups using non-negative matrix factorization (NMF) clustering. Results: Clustering of BL and DLBCL revealed six distinct genetic subgroups (Figure 1) with three primarily representing DLBCLs (DLBCL-1, DLBCL-2, and DLBCL-3) and three predominantly comprising BLs (M53-BL, IC-BL, and DGG-BL). The DLBCL-predominant subgroups partially overlapped with those previously described and resembled features of EZB and ST2-like subgroups. The frequency of aBLs within these subgroups was higher than that of pBL patients (p=0.0005). The new cluster M53-BL consists of both pBL (9/27) and aBL (13/27) samples and is characterized by the highest prevalence of mutations in TP53 accompanied by the paucity of other driver mutations but without the aneuploidy associated with the A53 subgroup described in DLBCL. Enrichment of EBV- samples in this cluster further corroborate our previous findings of TP53 mutations being associated with EBV- BL. IC-BL is characterized by mutations in ID3, CCND3, and SMARCA4. In contrast, DGG-BL, where 65% of the cluster consisted of EBV+ BL samples, had mutations in DDX3X, GNA13, and GNAI2. Using a linear model, we compared the rates of aSHM in BL genomes from all clusters and identified the DLBCL-3 cluster to harbor the highest aSHM rates at common sites while the M53-BL cluster harbored the lowest rates. To further establish the biological basis of unique clusters within BL, we conducted differential gene expression analyses between the two major BL genetic subgroups, DGG-BL and IC-BL. We identified a total of 86 differentially expressed genes between the two clusters (p.adj < 0.01 and |log2foldChange| > 1). Among the genes with the strongest differential expression were IRF4, SERPINA9, and TNFRSF13B. Each of these are notable as their expression is a component of the DLBCL cell-of-origin and double-hit signature classifiers. Further, we found IRF4 expression to be one of the strongest predictors of cluster membership, with high IRF4 expression associated with IC-BL membership. Using TP53 and ID3 mutations as a proxy for M53-BL and IC-BL clusters in aBL, we found mutations in TP53 to be associated with significantly inferior progression free survival (PFS) at 2 year follow up, while mutations in ID3 were associated with overall better PFS at 2 year follow up. Conclusion: This work identifies novel genetic subgroups within BL with characteristic genetic and gene expression differences and some bearing relationship to DLBCL subgroups. The three subgroups with predominantly BL samples (DGG-BL, IC-BL, and M53-BL) each comprised a mixture of aBL and pBL samples, confirming similar molecular features in these entities. The IC-BL cluster is associated with mutations in ID3 and CCND3, high IRF4 expression, and ID3 mutated cases exhibited significantly better outcomes. M53-BL is associated with TP53 mutations and inferior PFS in aBL, representing a subset of patients to be considered for novel treatment approaches. These findings highlight shared pathogenesis between aBL and pBL and establish genetic subtypes within BL that delineate cases with distinct molecular and clinical features. This provides a new framework for new diagnostic and therapeutic strategies. Figure 1 Figure 1. Disclosures Abramson: Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Bartlett: Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Casper: EUSA Pharma: Consultancy. Gerrie: Roche: Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astrazeneca: Honoraria, Research Funding; Sandoz: Honoraria. Grande: Sage Bionetworks: Current Employment. Mullighan: Illumina: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company. Noy: Epizyme: Consultancy; Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria. Scott: NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; AstraZeneca: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Rich/Genentech: Research Funding; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. . Morin: Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Epizyme: Patents & Royalties.
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- 2021
40. Complex Structural Variation Associated with Enhancer Hijacking and Loss of Tumor Suppressors in Mantle Cell Lymphoma
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David Scott, Marco A. Marra, Laura K. Hilton, Prasath Pararajalingam, Ari Melnick, Barbara Meissner, Kostiantyn Dreval, Ryan D. Morin, and Krysta M. Coyle
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Chemistry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,law.invention ,Structural variation ,law ,medicine ,Cancer research ,Suppressor ,Mantle cell lymphoma ,Enhancer - Abstract
Mantle cell lymphoma (MCL) is a rare, incurable mature B-cell lymphoma that can have either an aggressive or indolent clinical course. The hallmark aberration of MCL is the t(11;14)(q13;q32) translocation that places CCND1 under control of the immunoglobulin heavy chain (IGH) locus resulting in its constitutive expression. CCND1/IGH translocation occurs in nearly all MCL cases and arises during VDJ recombination. Whole genome sequencing (WGS) of MCLs has shown the prevalence of additional structural variations (SV), particularly in tumors with poor outcome. Complex rearrangements, such as chromothripsis and chromoplexy have been observed in MCL but their role in lymphomagenesis has not been determined. We hypothesized that some of these complex rearrangements afford a selective advantage to the tumor by disrupting tumor suppressor genes or by placing oncogenes in proximity to regulatory elements in cis, thereby resulting in ectopic expression. We performed WGS on tumor DNA extracted from 106 RCHOP-treated MCL patients. Matching ribosomal-depleted RNA-seq data was available for all tumor samples. Gene expression count values were obtained using Salmon and counts were normalized using the DESeq2 method. Structural variants were identified using a consensus between GRIDSS and Manta and these were analyzed to identify the topology of complex rearrangements using JaBbA. This allows the annotation of rearrangements such as chromothripsis and chromoplexy and enables the detection of genes near new regulatory elements through complex (multi-breakpoint) rearrangements. We supplemented this analysis by including 57 published classical and non-nodal leukemic MCL genomes. Chromothripsis and chromoplexy were observed in 8 and 12 tumors, respectively. The majority of the genomes were associated with isolated structural variations such as large deletions, inversions and reciprocal translocations were more common. Six genes (BCL10, TRAF6, TRAF3, MAP3K7, BTK, RELB) coding for canonical and non-canonical NFκB signaling proteins were found rearranged to within 1Mbp of a naïve B-cell super-enhancer region. The TRAF6 rearrangement was part of a chromothripsis and chromoplexy event involving both chr9 and chr11. A separate chromothripsis example involving chr1 placed each of BCL10 and NOTCH2 within 100-200kbp of super-enhancers. A 1Mbp region containing RELB was amplified and inserted into chr19p approximately 150kbp downstream a super-enhancer. An 800kbp deletion brought MAP3K7 to within 400kbp of a super-enhancer. DAZAP1, a gene known to be recurrently mutated in MCL, was translocated upstream to within 300kbp of a super-enhancer by t(5;19)(p13.3;p15.33). TRAF3 was translocated 400kbp upstream a super-enhancer by t(14;20)(q32.32;q13.13). None of the aforementioned SVs were associated with a detectable increase in expression of the affected gene. In contrast, we identified one genome in which the MYC oncogene was relocated 500kbp upstream of a super-enhancer via an unbalanced t(4;8)(q21.23;q24.21) translocation. In this case, MYC expression was in the 95 th percentile of MYC expression across the cohort. Focal deletions and amplifications were also found affecting lymphoma driver genes. Focal amplifications affecting 3q (34 tumors) and 5p (9 tumors), were among the most common recurrent events. These respectively affect the TERC and TERT genes, both involved in telomerase function. All tumors with TERT amplifications also showed TERC amplifications. TERC and TERT were expressed higher on average in amplified tumors than in unamplified tumors. Two tumors showed focal deletions affecting the 3' end of BIRC3. The focal deletion in one tumor was found to span to the 3' end of BIRC2 resulting in a BIRC2/BIRC3 fusion. Aberrant splicing across the two genes was evident in matching tumor RNA-seq data. Complex rearrangements in MCL have been found to link distant super-enhancer elements with a variety of lymphoma oncogenes. We noted a recurrence of such events affecting known regulators of NFκB signaling. We are using nanopore-based long-read PromethION sequencing to validate the structure of the derivative chromosome in these cases. Although these genes were not detectably overexpressed, deregulation of genes may be occurring by other means. The full extent of deregulation of NFκB and other oncogenic pathways will be revealed as complex rearrangements are studied in additional MCL tumors. Disclosures Coyle: Allakos, Inc.: Consultancy. Melnick: Epizyme: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; Janssen Pharmaceuticals: Research Funding; Constellation: Consultancy; KDAC Pharma: Membership on an entity's Board of Directors or advisory committees. Scott: BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; AstraZeneca: Consultancy; Abbvie: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; Rich/Genentech: Research Funding; Celgene: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding. Morin: Epizyme: Patents & Royalties; Celgene: Consultancy; Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees.
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- 2021
41. Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency
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Roberta Marra, Dario Consonni, Barbara Eleni Rosato, Elisa Fermo, Immacolata Andolfo, Anna Paola Marcello, Paola Bianchi, Stefania Martone, Anna Zaninoni, Achille Iolascon, Roberta Russo, Bruno Fattizzo, and Wilma Barcellini
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Iron homeostasis ,Chemistry ,Immunology ,medicine ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Cell biology ,Pyruvate kinase deficiency - Abstract
Iron loading anemias are characterized by ineffective erythropoiesis and iron overload. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias (CDA), and some forms of congenital hemolytic anemias. Among them pyruvate kinase deficiency (PKD) has been shown to develop iron overload also in absence of transfusions suggesting dyserythropoietic features. Moreover, severe forms can be misdiagnosed as CDA due to bone marrow abnormalities and ineffective erythropoiesis further supporting this evidences. The hormone erythroferrone (hERFE) is produced by erythroblasts in response to erythropoietin (EPO), and acts by suppressing hepcidin, thereby increasing iron absorption and mobilisation for erythropoiesis demand. The ERFE-hepcidin axis seems to play a crucial role in the pathogenesis of these disorders; an increased erythroferrone release by immature erythroid cells results in hepcidin suppression and secondary iron overload that could finally results in ineffective erythropoiesis and anemia. To investigate the pathophysiological basis of iron overload in PKD, we analysed the levels of hERFE, EPO, hepcidin, and soluble transferrin receptor (sTFR) in a large group of 41 PKD patients equally distributed by gender, age and severity. The results were analysed in comparison with two groups of patients affected by hemolytic anemia with overt dyserythropoiesis (42 patients with CDA type II) and with congenital hemolytic anemia due to RBC membrane defects (51 patients with hereditary spherocytosis [HS]), respectively. Demographic, hematologic, and biochemical features of the three groups of patients are reported in the table. Among the PKD patients, 18/41 were 6 tx/yrs). Mean ferritin levels at the time of the study were 546 ng/ml (range 59-4990), 15/41 patients requiring chelation therapy for iron overload developed also in absence of transfusions. As expected, CDAII patients showed decreased hepcidin levels (3.74 ng/mL; n.v. 17.25, P This study provides the first analysis of the main regulators of systemic iron homeostasis in PK deficiency compared either with the model of a structural RBC defect (HS) or with the typical model of dyserythropoietic anemia with ineffective erythropoiesis, such as CDAII. These data provide evidence of the dyserythropoietic features of PK deficiency, underlining the need of accurate diagnosis and paving the way of novel therapeutic approaches in PK deficiency. Zaninoni A. and Russo R. equally contributed to the study Figure 1 Figure 1. Disclosures Fattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Barcellini: Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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- 2021
42. The Copy Number Landscape of Relapsed and Refractory Diffuse Large B-Cell Lymphoma
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Rushton, Christopher, primary, Alcaide, Miguel, additional, Cheung, Matthew, additional, Michaud, Neil R, additional, Daigle, Scott, additional, Rys, Ryan N, additional, Arthur, Sarah E, additional, Zrymiak, Marquisa, additional, Davidson, Jordan, additional, Bushell, Kevin R, additional, Yu, Stephen, additional, Jain, Michael D., additional, Shepherd, Lois E., additional, Marra, Marco A., additional, Kuruvilla, John, additional, Crump, Michael, additional, Mann, Koren Kathleen, additional, Assouline, Sarit E, additional, Connors, Joseph M., additional, Steidl, Christian, additional, Johnson, Nathalie A, additional, Scott, David W., additional, and Morin, Ryan D, additional
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- 2020
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43. Integrative Analysis of Single-Cell RNA-Seq and ATAC-Seq Data across Treatment Time Points in Pediatric AML
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Wei, Lisa, primary, Trinh, Diane, additional, Ries, Rhonda E., additional, Jin, Dan, additional, Corbett, Richard D., additional, Smith, Jenny L., additional, Furlan, Scott N., additional, Meshinchi, Soheil, additional, and Marra, Marco A., additional
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- 2020
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44. Impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC
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Collinge, Brett J, primary, Ben-Neriah, Susana, additional, Chong, Lauren C., additional, Boyle, Merrill, additional, Jiang, Aixiang, additional, Miyata-Takata, Tomoko, additional, Farinha, Pedro, additional, Craig, Jeffrey W, additional, Slack, Graham W., additional, Ennishi, Daisuke, additional, Mottok, Anja, additional, Meissner, Barbara, additional, Chavez, Elizabeth A., additional, Gerrie, Alina S., additional, Villa, Diego, additional, Freeman, Ciara L., additional, Savage, Kerry J., additional, Sehn, Laurie H., additional, Morin, Ryan D., additional, Mungall, Andrew J, additional, Gascoyne, Randy D., additional, Marra, Marco A., additional, Connors, Joseph M, additional, Steidl, Christian, additional, and Scott, David W., additional
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- 2020
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45. The Copy Number Landscape of Relapsed and Refractory Diffuse Large B-Cell Lymphoma
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Lois E. Shepherd, Stephen Yu, Ryan N Rys, Ryan D. Morin, Kevin Bushell, Sarit Assouline, Jordan Davidson, Koren K. Mann, John Kuruvilla, Sarah E. Arthur, Nathalie A. Johnson, David Scott, Michael Crump, Christian Steidl, Christopher Rushton, Miguel Alcaide, Joseph M. Connors, Marco A. Marra, Marquisa Zrymiak, Michael D. Jain, Matthew C. Cheung, Scott R. Daigle, and Neil R Michaud
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Oncology ,medicine.medical_specialty ,Internal medicine ,Immunology ,Treatment outcome ,medicine ,Overall survival ,Treatment strategy ,Current employment ,Cell Biology ,Hematology ,Treatment resistance ,Biochemistry - Abstract
Introduction Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) are treated with standard frontline immunochemotherapy (R-CHOP). However, for cases where R-CHOP fails (relapsed-refractory DLBCL, rrDLBCL), prognosis is extremely poor, with 2-year overall survival of 20-40%. The successful development of new therapies may be hampered by our limited understanding of the genetic and molecular mechanisms underpinning treatment resistance. For example, recent data from our group has highlighted novel mutations that emerge following treatment with R-CHOP. The contribution of copy-number variations (CNVs) towards treatment resistance has not yet been thoroughly explored. A more complete characterization of these genetic alterations may lead to new prognostic biomarkers or treatment strategies. Methods We analyzed exome sequencing data from 59 rrDLBCL cases derived from either tissue biopsies or liquid biopsies collected after relapse, including both unpublished and previously published cases (Schmitz et al. (2018) NEJM 378:1396-1407 and Morin et al. (2016) Clin Can Res 22(9)). We separately performed low-pass whole-genome sequencing (lpWGS, 0.1-1x coverage) on 45 rrDLBCL liquid biopsies with ctDNA levels insufficient for exome-based analysis, for a total of 104 cases with copy-number information. We identified CNVs from exome and lpWGS data using Sequenza and ichorCNA, respectively. Next, we identified significant peaks of recurrent gains and losses using GISTIC2. Comparison of these peaks to CNVs in a previously published diagnostic DLBCL cohort (Schmitz et al. (2018) NEJM 378:1396-1407) enabled the identification of events that were significantly more prevalent in rrDLBCL. Results Overall, the landscape of CNVs in rrDLBCL is reminiscent of diagnostic DLBCL, with recurrent amplifications of chromosome 7 (43/104, 41.3%) and 18q (42/104, 40.4%) and recurrent deletions of 6q (25/104, 24.0%) and 17p13 (39/104, 37.5%). We identified nine regions enriched for recurrent amplifications or deletions among rrDLBCLs. These include deletions of 17p13.1 (20.4% in diagnostic biopsies vs 41.3% of rrDLBCLs, q=8.53x10-5) and recurrent amplifications of 8q24 (18.5% vs 42.3%, q=5.72x10-7) and 7p22 (27.2% vs 57.9%, q=6.29x10-8). Many of these peaks represent focal events that are exceedingly rare in diagnostic DLBCL and do not contain established lymphoma-associated genes, including amplifications affecting 700kb of 6p11.2 (2.03% vs 7.69%, q=0.0178) and 500kb of 19p13.3 (6.7% vs 31.7%, q=9.99x10-10). Notably, the 6p11.2 amplifications were associated with inferior progression-free survival following R-CHOP (p=0.02), with most tumors harboring this alteration relapsing within 12 months. We also identified a novel, recurrent deletion affecting a 20mb region of 5q (2.78% vs 10.6%, q=0.00604) which was significantly deleted in rrDLBCL. For tumors with additional samples collected prior to R-CHOP and following salvage therapy, deletions of 5q appeared to emerge following frontline therapy and persisted after subsequent treatments, suggesting they may contribute to treatment resistance. Discussion The 17p13.1 deletion enriched in rrDLBCL encompasses TP53, which is a common target of somatic point mutations in rrDLBCL and associated with inferior treatment outcomes. The amplification of 8q24 and 7p22 include MYC and GNA12/CARD11, respectively, although these large events encompass numerous additional genes which may be the target of such events. Curiously, the focal 6p11.2 amplification only overlaps a handful of genes including miR_598, which has been predicted to target CD27 and CD38 and whose expression is upregulated in B-cell cell lines (Lawrie et al. (2008) Leukemia 22:1440-2446). Further investigation and validation of these events and their corresponding targets will provide insight into the biology of rrDLBCL and may reveal novel therapeutic targets. Disclosures Michaud: Epizyme: Current Employment. Daigle:Epizyme: Current Employment. Jain:Kite/Gilead: Consultancy; Novartis: Consultancy. Kuruvilla:Merck: Consultancy, Honoraria; Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Honoraria; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Antengene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; TG Therapeutics: Honoraria. Crump:Servier: Consultancy; Roche: Consultancy; Kite/Gilead: Consultancy. Assouline:BeiGene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; Pfizer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Steidl:Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy; Bayer: Consultancy; Curis Inc: Consultancy. Johnson:AbbVie: Research Funding; Roche/Genentech, Merck: Honoraria; Roche/Genentech, Merck, Bristol-Myers Squibb, AbbVie: Consultancy. Scott:NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Janssen: Consultancy, Research Funding; Roche/Genentech: Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Morin:Celgene: Consultancy.
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46. Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing
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Pararajalingam, Prasath, primary, Coyle, Krysta M., additional, Arthur, Sarah E., additional, Thomas, Nicole, additional, Alcaide, Miguel, additional, Meissner, Barbara, additional, Boyle, Merrill, additional, Qureshi, Quratulain, additional, Grande, Bruno M., additional, Rushton, Christopher, additional, Slack, Graham W., additional, Mungall, Andrew J., additional, Tam, Constantine S., additional, Agarwal, Rishu, additional, Dawson, Sarah-Jane, additional, Lenz, Georg, additional, Balasubramanian, Sriram, additional, Gascoyne, Randy D., additional, Steidl, Christian, additional, Connors, Joseph, additional, Villa, Diego, additional, Audas, Timothy E., additional, Marra, Marco A., additional, Johnson, Nathalie A., additional, Scott, David W., additional, and Morin, Ryan D., additional
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- 2020
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47. Placental myeloid sarcoma
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Marra, Andrea, primary and Martino, Giovanni, primary
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- 2020
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48. TP53 Expression Correlates with TP53 Mutations and Is an Independent Predictor of Clinical Outcome in Patients with DLBCL Treated with R-CHOP
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Farinha, Pedro, primary, Ennishi, Daisuke, additional, Mottok, Anja, additional, Ben-Neriah, Susana, additional, Meissner, Barbara, additional, Boyle, Merrill, additional, Craig, Jeffrey W., additional, Slack, Graham W, additional, Villa, Diego, additional, Savage, Kerry J, additional, Sehn, Laurie H, additional, Morin, Ryan D., additional, Marra, Marco A., additional, Connors, Joseph M., additional, Gascoyne, Randy D., additional, Steidl, Christian, additional, and Scott, David W., additional
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- 2019
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49. Transcriptome Analysis of Pediatric AML Reveals Non Protein-Coding RNAs Associated with Poor Survival Outcome and Treatment Resistance
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Wei, Lisa, primary, Ries, Rhonda E., additional, Plettner, Patrick, additional, Mungall, Karen, additional, Mungall, Andrew J., additional, Meshinchi, Soheil, additional, and Marra, Marco A., additional
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- 2019
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50. Molecular Correlates of Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma
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Kridel, Robert, primary, Isaev, Keren, additional, Ennishi, Daisuke, additional, Skinnider, Brian, additional, Mungall, Karen, additional, Mungall, Andrew J., additional, Bakhtiari, Mehran, additional, Tremblay-Lemay, Rosemarie, additional, Meissner, Barbara, additional, Ben-Neriah, Susana, additional, Boyle, Merrill, additional, Villa, Diego, additional, Marra, Marco A., additional, Steidl, Christian, additional, Gascoyne, Randy D., additional, Savage, Kerry J, additional, and Scott, David W., additional
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- 2019
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