New Results
Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design
View ORCID ProfileJo Lynne Rokita, Komal S. Rathi, Maria F. Cardenas, Kristen A. Upton, Joy Jayaseelan, Katherine L. Cross, Jacob Pfeil, Laura E. Ritenour, Apexa Modi, Alvin Farrel, View ORCID ProfileGregory P. Way, View ORCID ProfileNathan M. Kendsersky, Khushbu Patel, View ORCID ProfileGonzalo Lopez, View ORCID ProfileZalman Vaksman, View ORCID ProfileChelsea Mayoh, Jonas Nance, Kristyn McCoy, View ORCID ProfileMichelle Haber, Kathryn Evans, Hannah McCalmont, Katerina Bendak, Julia W. Böhm, Glenn M. Marshall, Vanessa Tyrrell, View ORCID ProfileKarthik Kalletla, Frank K. Braun, Lin Qi, Yunchen Du, Huiyuan Zhang, Holly B. Lindsay, Sibo Zhao, Jack Shu, Patricia Baxter, Christopher Morton, Dias Kurmashev, Siyuan Zheng, Yidong Chen, Jay Bowen, Anthony C. Bryan, Kristen M. Leraas, Sara E. Coppens, HarshaVardhan Doddapaneni, Zeineen Momin, Wendong Zhang, Gregory I. Sacks, Lori S. Hart, Kateryna Krytska, Yael P. Mosse, Gregory J. Gatto, Yolanda Sanchez, View ORCID ProfileCasey S. Greene, Sharon J. Diskin, Olena Morozova Vaske, View ORCID ProfileDavid Haussler, Julie M. Gastier-Foster, E. Anders Kolb, Richard Gorlick, Xiao-Nan Li, C. Patrick Reynolds, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, Pichai Raman, David A. Wheeler, John M. Maris
doi: https://doi.org/10.1101/566455
Jo Lynne Rokita
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
3Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Komal S. Rathi
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
3Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Maria F. Cardenas
4Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
Kristen A. Upton
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
Joy Jayaseelan
4Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
Katherine L. Cross
5Guardian Forensic Sciences, Abington, PA, 19001, USA
Jacob Pfeil
6UC Santa Cruz Genomics Institute, Santa Cruz, CA, 95064, USA
Laura E. Ritenour
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
7Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104, USA
Apexa Modi
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
8Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104, USA
Alvin Farrel
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Gregory P. Way
8Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104, USA
Nathan M. Kendsersky
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
9Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA
Khushbu Patel
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Gonzalo Lopez
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Zalman Vaksman
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Chelsea Mayoh
10Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Australia
Jonas Nance
11Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430, USA
Kristyn McCoy
11Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430, USA
Michelle Haber
10Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Australia
Kathryn Evans
10Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Australia
Hannah McCalmont
10Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Australia
Katerina Bendak
10Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Australia
Julia W. Böhm
10Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Australia
Glenn M. Marshall
10Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Australia
12Sydney Children’s Hospital, Sydney, Australia
Vanessa Tyrrell
13Children’s Cancer Institute, Australia
Karthik Kalletla
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
3Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Frank K. Braun
14Texas Children’s Cancer and Hematology Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Lin Qi
15Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX, 77030, USA
16Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Yunchen Du
15Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX, 77030, USA
16Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Huiyuan Zhang
15Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX, 77030, USA
16Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Holly B. Lindsay
15Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX, 77030, USA
16Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Sibo Zhao
15Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX, 77030, USA
16Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Jack Shu
15Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX, 77030, USA
16Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Patricia Baxter
15Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX, 77030, USA
16Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Christopher Morton
17Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
Dias Kurmashev
18Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, 78229, USA
Siyuan Zheng
18Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, 78229, USA
Yidong Chen
18Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, 78229, USA
Jay Bowen
19The Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43205, USA
Anthony C. Bryan
19The Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43205, USA
Kristen M. Leraas
19The Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43205, USA
Sara E. Coppens
19The Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43205, USA
HarshaVardhan Doddapaneni
4Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
Zeineen Momin
4Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
Wendong Zhang
20Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Gregory I. Sacks
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
Lori S. Hart
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
Kateryna Krytska
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
Yael P. Mosse
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
Gregory J. Gatto
21Department of Global Health Technologies, RTI International, Research Triangle Park, NC 27709, USA
Yolanda Sanchez
22Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA
23Norris Cotton Cancer Center, Lebanon, NH, 03766, USA
Casey S. Greene
24Childhood Cancer Data Lab, Alex’s Lemonade Stand Foundation, Philadelphia, PA, 19102, USA
9Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA
Sharon J. Diskin
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Olena Morozova Vaske
25Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA
6UC Santa Cruz Genomics Institute, Santa Cruz, CA, 95064, USA
David Haussler
6UC Santa Cruz Genomics Institute, Santa Cruz, CA, 95064, USA
26Howard Hughes Medical Institute, University of California, Santa Cruz, CA, 95064, USA
Julie M. Gastier-Foster
19The Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43205, USA
27The Ohio State University College of Medicine, Departments of Pathology and Pediatrics, Columbus, OH, 43210, USA
E. Anders Kolb
28Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, 19107, USA
29Nemours Center for Cancer and Blood Disorders, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA
Richard Gorlick
20Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Xiao-Nan Li
15Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX, 77030, USA
16Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
30Division of Hematology, Oncology, Neuro-oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, 60611, USA
31Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
C. Patrick Reynolds
11Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430, USA
Raushan T. Kurmasheva
18Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, 78229, USA
Peter J. Houghton
18Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, 78229, USA
Malcolm A. Smith
32National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
Richard B. Lock
13Children’s Cancer Institute, Australia
Pichai Raman
2Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
3Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
David A. Wheeler
4Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
John M. Maris
1Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
Summary
Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors for TP53 and NF1 inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer.
Highlights
Multiplatform genomic analysis defines landscape of 261 pediatric cancer patient derived xenograft (PDX) models
Pediatric patient derived xenografts faithfully recapitulate relapsed disease
Inferred TP53 pathway inactivation correlates with pediatric cancer copy number burden
Somatic mutational signatures predict impaired DNA repair across multiple histologies
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Posted March 30, 2019.
Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design
Jo Lynne Rokita, Komal S. Rathi, Maria F. Cardenas, Kristen A. Upton, Joy Jayaseelan, Katherine L. Cross, Jacob Pfeil, Laura E. Ritenour, Apexa Modi, Alvin Farrel, Gregory P. Way, Nathan M. Kendsersky, Khushbu Patel, Gonzalo Lopez, Zalman Vaksman, Chelsea Mayoh, Jonas Nance, Kristyn McCoy, Michelle Haber, Kathryn Evans, Hannah McCalmont, Katerina Bendak, Julia W. Böhm, Glenn M. Marshall, Vanessa Tyrrell, Karthik Kalletla, Frank K. Braun, Lin Qi, Yunchen Du, Huiyuan Zhang, Holly B. Lindsay, Sibo Zhao, Jack Shu, Patricia Baxter, Christopher Morton, Dias Kurmashev, Siyuan Zheng, Yidong Chen, Jay Bowen, Anthony C. Bryan, Kristen M. Leraas, Sara E. Coppens, HarshaVardhan Doddapaneni, Zeineen Momin, Wendong Zhang, Gregory I. Sacks, Lori S. Hart, Kateryna Krytska, Yael P. Mosse, Gregory J. Gatto, Yolanda Sanchez, Casey S. Greene, Sharon J. Diskin, Olena Morozova Vaske, David Haussler, Julie M. Gastier-Foster, E. Anders Kolb, Richard Gorlick, Xiao-Nan Li, C. Patrick Reynolds, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, Pichai Raman, David A. Wheeler, John M. Maris
bioRxiv 566455; doi: https://doi.org/10.1101/566455
Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design
Jo Lynne Rokita, Komal S. Rathi, Maria F. Cardenas, Kristen A. Upton, Joy Jayaseelan, Katherine L. Cross, Jacob Pfeil, Laura E. Ritenour, Apexa Modi, Alvin Farrel, Gregory P. Way, Nathan M. Kendsersky, Khushbu Patel, Gonzalo Lopez, Zalman Vaksman, Chelsea Mayoh, Jonas Nance, Kristyn McCoy, Michelle Haber, Kathryn Evans, Hannah McCalmont, Katerina Bendak, Julia W. Böhm, Glenn M. Marshall, Vanessa Tyrrell, Karthik Kalletla, Frank K. Braun, Lin Qi, Yunchen Du, Huiyuan Zhang, Holly B. Lindsay, Sibo Zhao, Jack Shu, Patricia Baxter, Christopher Morton, Dias Kurmashev, Siyuan Zheng, Yidong Chen, Jay Bowen, Anthony C. Bryan, Kristen M. Leraas, Sara E. Coppens, HarshaVardhan Doddapaneni, Zeineen Momin, Wendong Zhang, Gregory I. Sacks, Lori S. Hart, Kateryna Krytska, Yael P. Mosse, Gregory J. Gatto, Yolanda Sanchez, Casey S. Greene, Sharon J. Diskin, Olena Morozova Vaske, David Haussler, Julie M. Gastier-Foster, E. Anders Kolb, Richard Gorlick, Xiao-Nan Li, C. Patrick Reynolds, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, Pichai Raman, David A. Wheeler, John M. Maris
bioRxiv 566455; doi: https://doi.org/10.1101/566455
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