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Activation of proto-oncogenes by disruption of chromosome neighborhoods

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE68978 | GEO | 2015/05/28

SECONDARY ACCESSION(S): PRJNA284247

REPOSITORIES: GEO

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Activation of proto-oncogenes by disruption of chromosome neighborhoods

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-05-28 | E-GEOD-68978 | biostudies-arrayexpress

Activation of proto-oncogenes by disruption of chromosome neighborhoods.

Project description:Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.

| S-EPMC4884612 | biostudies-literature

Activation of proto-oncogenes by disruption of chromosome neighborhoods [chIA-PET]

Project description:Mutations such as gene fusion, translocation and focal amplification are a frequent cause of proto-oncogene activation during tumorigenesis, but such mutations do not explain all cases of proto-oncogene activation. Here we show that disruption of local chromosome conformation can also activate proto-oncogenes in human cells. We mapped chromosome structures in T-cell acute lymphoblastic leukemia (T-ALL), and found that active oncogenes and silent proto-oncogenes generally occur within insulated neighborhoods formed by the looping of two interacting CTCF sites co-occupied by cohesin. Recurrent microdeletions frequently overlap neighborhood boundary sites in T-ALL genomes, and we demonstrate that site-specific perturbation of loop boundaries is sufficient to activate the respective proto-oncogenes in non-malignant cells. We found somatic genomic rearrangements affecting loop boundaries in many cancers. These results suggest that chromosome structural organization is fundamental to identify functional somatic alterations in cancer genomes.

2015-05-28 | GSE68977 | GEO