Genomic landscape of 261 childhood cancer patient-derived xenograft models

Rokita, J. L.; Rathi, K. S.; Cardenas, M. F.; Upton, K. A.; Jayaseelan, J.; Cross, K. L.; Pfeil, J.; Ritenour, L. E.; Modi, A.; Farrel, A.; Way, G. P.; Kendsersky, N. M.; Patel, K.; Lopez, G.; Vaksman, Z.; Mayoh, C.; Nance, J.; McCoy, K.; Haber, M.; Evans, K.; McCalmont, H.; Bendak, K.; Bohm, J. W.; Marshall, G. M.; Tyrrell, V.; Kalletla, K.; Braun, F. K.; Qi, L.; Du, Y.; Zhang, H.; Lindsay, H. B.; Zhao, S.; Shu, J.; Baxter, P.; Morton, C.; Kurmashev, D.; Zheng, S.; Chen, Y.; Bowen, J.; Bryan, A. C.; Leraas, K. M.; Coppens, S. E.; Doddapaneni, H.; Momin, Z.; Zhang, W.; Sacks, G. I.; Hart, L. S

doi:10.1101/566455

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bioRxiv · 10.1101/566455

Genomic landscape of 261 childhood cancer patient-derived xenograft models

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Abstract

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.\n\nHighlightsO_LIMultiplatform genomic analysis defines landscape of 261 pediatric cancer patient derived xenograft (PDX) models\nC_LIO_LIPediatric patient derived xenografts faithfully recapitulate relapsed disease\nC_LIO_LIInferred TP53 pathway inactivation correlates with pediatric cancer copy number burden\nC_LIO_LISomatic mutational signatures predict impaired DNA repair across multiple histologies\nC_LI

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Rokita, J. L., Rathi, K. S., Cardenas, M. F., Upton, K. A., Jayaseelan, J., Cross, K. L., Pfeil, J., Ritenour, L. E., Modi, A., Farrel, A., Way, G. P., Kendsersky, N. M., Patel, K., Lopez, G., Vaksman, Z., Mayoh, C., Nance, J., McCoy, K., Haber, M., Evans, K., McCalmont, H., Bendak, K., Bohm, J. W., Marshall, G. M., Tyrrell, V., Kalletla, K., Braun, F. K., Qi, L., Du, Y., Zhang, H., Lindsay, H. B., Zhao, S., Shu, J., Baxter, P., Morton, C., Kurmashev, D., Zheng, S., Chen, Y., Bowen, J., Bryan, A. C., Leraas, K. M., Coppens, S. E., Doddapaneni, H., Momin, Z., Zhang, W., Sacks, G. I., Hart, L. S. 2019-03-06. Genomic landscape of 261 childhood cancer patient-derived xenograft models. https://doi.org/10.1101/566455

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