The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
A novel retinoblastoma therapy from genomic and epigenetic analyses
Open accessAbstract
Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss. The retinoblastoma genome is shown to be stable, but multiple cancer pathways are identified that are epigenetically deregulated, providing potential new therapeutic targets. Retinoblastoma is a rare and aggressive childhood cancer of the retina caused by loss of the RB1 gene. Whole-genome sequencing of four retinoblastomas now shows that the retinoblastoma genome is relatively stable, with a mutational rate among the lowest reported in human cancers and a remarkable lack of mutations in other tumour suppressor/oncogenic pathways. However, RB1 loss is associated with epigenetic deregulation of several cancer pathways. Significantly, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. A small-molecule inhibitor of SYK induced retinoblastoma tumour cell death in vitro and in vivo.
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Cites
Hallmarks of Cancer: The Next Generation
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A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma
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“When the RB1 gene was first cloned, it was found to undergo biallelic inactivation in virtually all retinoblastoma tumour”
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One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma
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“Tumour SJRB001 had four structural variations (two DEL and ins INS) including a gain of a region of chromosome 2 spanning MYCN ( Supplementary Table 12 ), and the only chromosomal lesion in SJRB002 was a gain of chromosome 6p, which occurs in about 40% of human retinoblastoma”
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RB acute loss induces centrosome amplification and aneuploidy in murine primary fibroblasts
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Cited by
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Restifo, N. P., Dudley, M. E., & Rosenberg, S. A. (2012) · Nature Reviews Immunology · doi:10.1038/nri3191 · Cited by 1,688
The landscape of genomic alterations across childhood cancers
ICGC PedBrain-Seq Project, Gröbner, S. N., ICGC MMML-Seq Project, Worst, B. C., Weischenfeldt, J., Buchhalter, I., Kleinheinz, K., Rudneva, V. A., Johann, P. D., Balasubramanian, G. P., et al. (2018) · Nature · doi:10.1038/nature25480 · Cited by 1,572
Self-citationGermline Mutations in Predisposition Genes in Pediatric Cancer
Zhang, J., Walsh, M. F., Wu, G., Edmonson, M. N., Gruber, T. A., Easton, J., Hedges, D., Ma, X., Zhou, X., Yergeau, D. A., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1508054 · Cited by 1,345
Self-citationPan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours
Ma, X., Liu, Y., Liu, Y., Alexandrov, L. B., Edmonson, M. N., Gawad, C., Zhou, X., Li, Y., Rusch, M. C., Easton, J., et al. (2018) · Nature · doi:10.1038/nature25795 · Cited by 901
Self-citationEpigenetic modulators, modifiers and mediators in cancer aetiology and progression
Feinberg, A. P., Koldobskiy, M. A., & Göndör, A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.13 · Cited by 841
Metadata
- Authors
- Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., Ulyanov, A., Wu, G., Wilson, M., Wang, J., Brennan, R., Rusch, M., Manning, A. L., Ma, J., Easton, J., Shurtleff, S., Mullighan, C., Pounds, S., Mukatira, S., Gupta, P., Neale, G., Zhao, D., Lu, C., Fulton, R. S., Fulton, L. L., Hong, X., Dooling, D. J., Ochoa, K., Naeve, C., Dyson, N. J., Mardis, E. R., Bahrami, A., Ellison, D., Wilson, R. K., Downing, J. R., & Dyer, M. A.
- Venue
- Nature
- Published
- 2012-01
- Volume
- 481
- Issue
- 7381
- Pages
- 329-334
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2142877023
- Cited by
- 516
- References
- 6
- FWCI
- 53.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., Ulyanov, A., Wu, G., Wilson, M., Wang, J., Brennan, R., Rusch, M., Manning, A. L., Ma, J., Easton, J., Shurtleff, S., Mullighan, C., Pounds, S., Mukatira, S., . . . Dyer, M. A. (2012). A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. https://doi.org/10.1038/nature10733
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