Scientific Advances: A childhood cancer dependency map

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Kimberly Stegmaier from the Dana Farber Cancer Research Institute led a tour-de-force endeavor to characterize unique genetic vulnerabilities in childhood cancer cell lines. In total, 82 genome-wide CRISPR screens were performed using the Avana lentiviral gRNA library, targeting over 18,000 human genes. The authors focused on pediatric cell lines from solid tumors, such as Ewing sarcoma, medulloblastoma, neuroblastoma and osteosarcoma, because therapeutic progress against these childhood cancers has been relatively limited. Data from the CRISPR screens were combined with whole exome and RNA seq analysis to generate the most comprehensive pediatric tumor dependency map to date.

Contrary to expectations, the authors found that the number of genetic vulnerabilities in pediatric tumor cell lines was similar to adult cancers, despite a much lower mutation load observed in childhood malignancies. Identified vulnerabilities include the methyltransferase EZH2 (neuroblastoma), MDM2 / MDM4 (Ewing sarcoma, rhabdoid tumors), receptor tyrosine kinases ALK / BRAF (rhabdoid tumors), and SMARCB1-associated proteasome dependency. Importantly, a considerable number of identified genetic vulnerabilities were unique to pediatric cancers, in correlation with unique genetic drivers in childhood cancer. The pediatric cancer dependency map will greatly facilitate the development of personalized treatments based on genetic signatures in childhood tumors.

For more information, see:
Dharia, N.V., Kugener, G., Guenther, L.M. et al. (2021) A first-generation pediatric cancer dependency map. Nat. Genet. https://doi.org/10.1038/s41588-021-00819-w

Keywords: CRISPR screen, pediatric cancer, genetic vulnerability

Also, see our ‘At a glance’ section for more information on recent genome-wide CRISPR screens in cancer cells.

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