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