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Human Molecular Genetics, 2003, Vol. 12, No. 5 535-549
© 2003 Oxford University Press

Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site

Gary A. Ulaner1, Thanh H. Vu1, Tao Li1, Ji-Fan Hu1, Xiao-Ming Yao1, Youwen Yang1, Richard Gorlick2, Paul Meyers2, John Healey3, Marc Ladanyi4 and Andrew R. Hoffman1,*

1Medical Service, VA Palo Alto Health Care System, and Department of Medicine, Stanford University, Palo Alto, CA, 94304, USA, 2Department of Pediatrics, 3Department of Orthopaedics and 4Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY 10021, USA

Received November 4, 2002; Revised December 3, 2002; Accepted December 11, 2002

The adjacent insulin-like growth factor 2 (IGF2) and H19 genes are imprinted in most normal human tissues, but imprinting is often lost in tumors. The mechanisms involved in maintenance of imprinting (MOI) and loss of imprinting (LOI) are unresolved. We show here that osteosarcoma (OS) tumors with IGF2/H19 MOI exhibit allele-specific differential methylation of a CTCF-binding site upstream of H19. LOI of IGF2 or H19 in OS occurs in a mutually exclusive manner, and occurs with monoallelic expression of the other gene. Bisulfite sequencing reveals IGF2 LOI occurs with biallelic CpG methylation of the CTCF-binding site, while H19 LOI occurs with biallelic hypomethylation of this site. Our data demonstrate that IGF2 LOI and H19 LOI are accompanied by reciprocal methylation changes at a critical CTCF-binding site. We propose a model in which incomplete gain or loss of methylation at this CTCF-binding site during tumorigenesis explains the complex and often conflicting expression patterns of IGF2 and H19 in tumors.

* To whom correspondence should be addressed at: Medical Service, VA Palo Alto Medical Center, 3801 Miranda Ave., Palo Alto, CA 94304, USA. Tel: +1 6504935000 ext. 63930; Fax: +1 6508568024; Email: arhoffman{at}stanford.edu


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