A first-generation pediatric cancer dependency map.

Autor: Dharia NV; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA., Kugener G; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA., Guenther LM; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA., Malone CF; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA., Durbin AD; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA.; Department of Oncology, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN, USA., Hong AL; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA.; Department of Pediatrics, Emory University and Department of Hematology and Oncology, Children's Healthcare of Atlanta, Atlanta, GA, USA., Howard TP; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Bandopadhayay P; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA., Wechsler CS; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA., Fung I; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Warren AC; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Dempster JM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Krill-Burger JM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Paolella BR; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Moh P; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; University of Maryland, College Park, MD, USA., Jha N; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Tang A; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Montgomery P; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Boehm JS; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Hahn WC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Roberts CWM; Department of Oncology, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN, USA., McFarland JM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Tsherniak A; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Golub TR; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA., Vazquez F; Broad Institute of MIT and Harvard, Cambridge, MA, USA. vazquez@broadinstitute.org.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. vazquez@broadinstitute.org., Stegmaier K; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. kimberly_stegmaier@dfci.harvard.edu.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. kimberly_stegmaier@dfci.harvard.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. kimberly_stegmaier@dfci.harvard.edu.; Harvard Medical School, Boston, MA, USA. kimberly_stegmaier@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2021 Apr; Vol. 53 (4), pp. 529-538. Date of Electronic Publication: 2021 Mar 22.
DOI: 10.1038/s41588-021-00819-w
Abstrakt: Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were subjected to genome-scale CRISPR-Cas9 loss-of-function screening to identify genes required for cell survival. In contrast to the finding that pediatric cancers harbor fewer somatic mutations, we found a similar complexity of genetic dependencies in pediatric cancer cell lines compared to that in adult models. Findings from the pediatric cancer dependency map provide preclinical support for ongoing precision medicine clinical trials. The vulnerabilities observed in pediatric cancers were often distinct from those in adult cancer, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers.
Databáze: MEDLINE
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