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

Abstract：

: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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Dehainault C,Garancher A,Castéra L,Cassoux N,Aerts I,Doz F,Desjardins L,Lumbroso L,Montes de Oca R,Almouzni G,Stoppa-Lyonnet D,Pouponnot C,Gauthier-Villars M,Houdayer C

doi

10.1093/hmg/ddu245

subject

Has Abstract

pub_date

2014-10-01 00:00:00

pages

5243-50

issue

19

eissn

0964-6906

issn

1460-2083

pii

ddu245

journal_volume

23

pub_type

杂志文章

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