Methods of detecting insulator dysfunction and oncogene activation for screening, diagnosis and treatment of patients in need thereof

US11339442B2 · kind B2 · utility

Assignee

• The General Hospital Corporation · US

Inventors

• Bradley E. Bernstein · Cambridge, US
• Yotam Drier · Cambridge, US
• William Flavahan · Malden, US
• Daniel Tarjan · Cambridge, US

Key dates

• Filing date: Dec 14, 2016
• Grant date: May 24, 2022
• Expiry date: Dec 14, 2036

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C12Q2600/156
• WIPO field: Biotechnology
• WIPO sector: Chemistry

Abstract

The present application generally to the diagnosis and treatment of diseases resulting from the alteration of chromatin boundaries between topologically-associated domains. In particular, the present application relates to detection of mutations causing DNA hypermethylation phenotypes, CpG methylation within CTCF binding motifs, and aberrant gene expression caused by altered chromatin topology. Applicants show that IDH mutant gliomas exhibit hyper-methylation at CTCF binding sites, compromising binding of this methylation-sensitive insulator protein. Applicants also demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Thus, Applicants have uncovered that IDH mutations may promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.