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Activation of proto-oncogenes by disruption of chromosome neighborhoods

2016; American Association for the Advancement of Science; Volume: 351; Issue: 6280 Linguagem: Inglês

10.1126/science.aad9024

1095-9203

Denes Hnisz, Abraham S. Weintraub, Daniel S. Day, Anne-Laure Valton, Rasmus O. Bak, Charles H. Li, Johanna Goldmann, Bryan R. Lajoie, Zi Peng Fan, Alla A. Sigova, Jessica Reddy, Diego Borges-Rivera, Tong Ihn Lee, Rudolf Jaenisch, Matthew H. Porteus, Job Dekker, Richard A. Young,

Cancer Genomics and Diagnostics

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.