Cell Reports (Nov 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. Egolf,
- Gregory P. Way,
- Alvin Farrel,
- Nathan M. Kendsersky,
- Khushbu Patel,
- Krutika S. Gaonkar,
- Apexa Modi,
- Esther R. Berko,
- 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
Affiliations
- Jo Lynne Rokita
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA; Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Komal S. Rathi
- Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Maria F. Cardenas
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Kristen A. Upton
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA
- Joy Jayaseelan
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Katherine L. Cross
- Guardian Forensic Sciences, Abington, PA 19001, USA
- Jacob Pfeil
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
- Laura E. Egolf
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
- Gregory P. Way
- Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
- Alvin Farrel
- Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Nathan M. Kendsersky
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
- Khushbu Patel
- Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Krutika S. Gaonkar
- Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Apexa Modi
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA; Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
- Esther R. Berko
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA
- Gonzalo Lopez
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA; Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Zalman Vaksman
- Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Chelsea Mayoh
- Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Jonas Nance
- Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX 79430, USA
- Kristyn McCoy
- Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX 79430, USA
- Michelle Haber
- Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Kathryn Evans
- Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Hannah McCalmont
- Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Katerina Bendak
- Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Julia W. Böhm
- Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Glenn M. Marshall
- Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia; Sydney Children’s Hospital, Sydney, NSW, Australia
- Vanessa Tyrrell
- Children’s Cancer Institute, Kensington, NSW, Australia
- Karthik Kalletla
- Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Frank K. Braun
- Texas Children’s Cancer and Hematology Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Lin Qi
- Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Yunchen Du
- Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Huiyuan Zhang
- Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Holly B. Lindsay
- Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Sibo Zhao
- Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Jack Shu
- Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Patricia Baxter
- Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Christopher Morton
- Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Dias Kurmashev
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
- Siyuan Zheng
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
- Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
- Jay Bowen
- The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Anthony C. Bryan
- The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Kristen M. Leraas
- The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Sara E. Coppens
- The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- HarshaVardhan Doddapaneni
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Zeineen Momin
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Wendong Zhang
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Gregory I. Sacks
- Division 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
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA
- Kateryna Krytska
- Division 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
- Division 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
- Department of Global Health Technologies, RTI International, Research Triangle Park, NC 27709, USA
- Yolanda Sanchez
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03766, USA
- Casey S. Greene
- Childhood Cancer Data Lab, Alex’s Lemonade Stand Foundation, Philadelphia, PA 19102, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
- Sharon J. Diskin
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA; Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Olena Morozova Vaske
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
- David Haussler
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Howard Hughes Medical Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
- Julie M. Gastier-Foster
- The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; The Ohio State University College of Medicine, Departments of Pathology and Pediatrics, Columbus, OH 43210, USA
- E. Anders Kolb
- Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA; Nemours Center for Cancer and Blood Disorders, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA
- Richard Gorlick
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Xiao-Nan Li
- Preclinical Neurooncology Research Program, Texas Children’s Cancer Research Center, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Hematology, Oncology, Neuro-oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- C. Patrick Reynolds
- Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX 79430, USA
- Raushan T. Kurmasheva
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
- Peter J. Houghton
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
- Malcolm A. Smith
- National Cancer Institute, NIH, Bethesda, MD 20814, USA
- Richard B. Lock
- Children’s Cancer Institute, Kensington, NSW, Australia
- Pichai Raman
- Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- David A. Wheeler
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- John M. Maris
- Division of Oncology, Children’s Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA; Corresponding author
- Journal volume & issue
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Vol. 29,
no. 6
pp. 1675 – 1689.e9
Abstract
Summary: Accelerating cures for children with cancer remains an immediate challenge as a result of 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)—many of which are refractory to current standard-of-care treatments—from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer. : Rokita et. al provide an extensively annotated genomic dataset of somatic oncogenic regulation across 37 distinct pediatric malignancies. The 261 patient-derived xenograft models are available to the scientific community, and the genomic annotations will enable rational preclinical agent prioritization and acceleration of therapeutic targets for early-phase pediatric oncology clinical trials. Keywords: pediatric cancer, patient-derived xenograft, relapse, whole-exome sequencing, transcriptome sequencing, copy number profiling, preclinical testing, classifier
