The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion.

Human molecular genetics 2014 Oct 1

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Retinoblastoma is a non-hereditary as well as an inherited pediatric tumor of the developing retina resulting from the inactivation of both copies of the RB1 tumor suppressor gene. Familial retinoblastoma is a highly penetrant genetic disease that usually develops by carrying germline mutations that inactivate one allele of the RB1 gene, leading to multiple retinoblastomas. However, large and complete germline RB1 deletions are associated with low or no tumor risk for reasons that remain unknown. In this study, we define a minimal genomic region associated with this low penetrance. This region encompasses few genes including MED4 a subunit of the mediator complex. We further show that retinoblastoma RB1 -/- cells cannot survive in the absence of MED4, both in vitro and in orthotopic xenograft models in vivo, therefore identifying MED4 as a survival gene in retinoblastoma. We propose that the contiguous loss of the adjacent retinoblastoma gene, MED4, explains the low penetrance in patients with large deletions that include both RB1 and MED4. Our findings also point to another synthetic lethal target in tumors with inactivated RB1 and highlight the importance of collateral damage in carcinogenesis. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Citation

Catherine Dehainault, Alexandra Garancher, Laurent Castéra, Nathalie Cassoux, Isabelle Aerts, François Doz, Laurence Desjardins, Livia Lumbroso, Rocío Montes de Oca, Geneviève Almouzni, Dominique Stoppa-Lyonnet, Celio Pouponnot, Marion Gauthier-Villars, Claude Houdayer. The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion. Human molecular genetics. 2014 Oct 1;23(19):5243-50