Evidence map›Paper›PMID 40112818›Full record

ArticleCell genomics2025

Recurrent breakpoints in the BRD4 locus reduce toxicity associated with gene amplification.

Jeremiah Wala, Simona Dalin, Sophie Webster, Ofer Shapira, John Busanovich, Shahab Sarmashghi, Rameen Beroukhim, Pratiti Bandopadhayay, Veronica Rendo

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell genomics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Jeremiah WalaDepartments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Simona DalinDepartments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Sophie WebsterDepartments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ofer ShapiraDepartments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
John BusanovichDepartments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Shahab SarmashghiBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Rameen BeroukhimDepartments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Pratiti BandopadhayayBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Veronica RendoDepartments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Immunology, Genetics, and Pathology, Uppsala University, 75185 Uppsala, Sweden. Electronic address: veronica.rendo@igp.uu.se.

Funding

Factors Shaping the Genomic Spectrum of Structural VariantsK99GM155595 · NIGMS · BROAD INSTITUTE, INC. · PI DALIN, SIMONA · 2024 to 2025
$324k
Differential resistance mechanisms to monofunctional vs bifunctional alkylating agents in gliomaF32CA261024 · NCI · BROAD INSTITUTE, INC. · PI DALIN, SIMONA · 2021 to 2023
$208k
NCI NIH HHS F32 CA261024NIGMS NIH HHS K99 GM155595
6 · The paper itself

Abstract

Recent work by the ICGC-PCAWG consortium identified recurrent focal deletions in the BRD4 gene, decreasing expression despite increased copy number. We show that these focal deletions occur in the context of cyclin E1 amplification in breast, ovarian, and endometrial cancers, and serve to disrupt BRD4 regulatory regions and gene expression across isoforms. We analyze open reading frame screen data and find that overexpression of BRD4 long (BRD4-L) and short isoform BRD4-S(a) impairs cell growth across cell lines. We confirm these results in OVSAHO ovarian cancer cells, where the overexpression of BRD4 isoforms significantly reduces tumor growth. Next, we mimic BRD4 focal deletions using CRISPR-Cas9 technology and show that these focal deletions rescue ovarian cancer cells from toxicity associated with BRD4 overexpression, suggesting that BRD4 levels must be fine-tuned for cancer cell proliferation. Our study provides experimental evidence for the first recurrent deletion reducing toxicity in cancer, expanding the landscape of cancer progression mechanisms.

Indexed as

Gene AmplificationNuclear ProteinsTranscription FactorsAnimalsBromodomain Containing ProteinsCell Cycle ProteinsCell Line, TumorCell ProliferationCRISPR-Cas SystemsCyclin EFemaleGene Expression Regulation, NeoplasticHumansMiceOvarian NeoplasmsProtein IsoformsBRD4 protein, humanBromodomain Containing ProteinsCell Cycle ProteinsCyclin ENuclear ProteinsProtein IsoformsTranscription FactorsBRD4breast cancerCRISPR-Cas9gene amplificationgene isoformsovarian cancerPCAWG consortiumstructural variantstoxic gene

Identifiers

PMID40112818
PMCPMC12008804

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.