A PUBLICATION FROM BROAD INSTITUTE OF MIT AND HARVARD
Last updated January 2021

A First-Generation Pediatric Cancer Dependency Map

Neekesh V. Dharia1,2,3,4, Guillaume Kugener3,#, Lillian M. Guenther1,2,3,4, Clare F. Malone1,2,3,4, Adam D. Durbin1,2,3,4,*, Andrew L. Hong1,2,3,4,6,@, Thomas P. Howard1,2,3,4,5, Pratiti Bandopadhayay1,2,3,4, Caroline S. Wechsler1,2,3,4, Iris Fung3, Allison C. Warren3, Joshua M. Dempster3, John M. Krill-Burger3, Brenton R. Paolella3, Phoebe Moh3,%, Nishant Jha3, Andrew Tang3, Philip Montgomery3, Jesse S. Boehm3, William C. Hahn3,4,5, Charles W. M. Roberts6, James M. McFarland3, Aviad Tsherniak3, Todd R. Golub1,2,3,4, Francisca Vazquez3,$, Kimberly Stegmaier1,2,3,4, $

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  2. Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA
  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA
  4. Harvard Medical School, Boston, MA, USA
  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  6. Department of Oncology, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN, USA
  7. # Current address: Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
  8. % Current address: University of Maryland, College Park, MD, USA
  9. * Current address: St. Jude Children’s Research Hospital, Memphis, TN, USA
  10. @ Current address: Department of Pediatrics, Emory University and Department of Hematology and Oncology, Children’s Healthcare of Atlanta, Atlanta, GA, USA
  11. $ Corresponding authors: Kimberly Stegmaier (Kimberly_Stegmaier@dfci.harvard.edu), Francisca Vazquez (vazquez@broadinstitute.org)

Abstract

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 adult models. Findings from the Pediatric Cancer Dependency Map provide pre-clinical support for ongoing precision medicine clinical trials. The vulnerabilities seen in pediatric cancers were often distinct from adult, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers.

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Selective dependencies in pediatric and adult solid tumor lines

Selective dependency genes demonstrate subsets that are more common in pediatric compared to adult cancer cell lines. Each row on the y-axis represents one of the selective dependencies (removing common essential and non-essential genes) ordered across the three subpanels by rate of dependency seen in adult cancer cell lines. The left subpanel shows the rate at which adult cell lines are dependent and the center subpanel shows the rate at which pediatric cell lines are dependent. The right subpanel demonstrates the difference in rate of dependency in pediatric versus adult cell lines with dependencies seen at greater frequency in pediatric cell lines colored red and those seen more frequently in adult cell lines as black. The bars in the center and right panels are colored by the contribution of each tumor type.

When a single gene is selected from the plot or search box, the frequency of dependency on that gene is depicted in pediatric and adult solid tumor types with at least 3 cell lines screened per type in polar bar graphs. The heights of the bars correspond to the fraction of cell lines of a particular tumor type that are dependent on the gene.

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