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Regional DNA Hypermethylation at D17S5 Precedes 17p Structural Changes in the Progression of Renal Tumors¹

Oncology Center [M. M., B. D. N., S. B. B.], Departments of Medicine [S. B. B.] and Urology [J. B., W. I.], and Human Genetics Program [M. M., S. B. B.], The Johns Hopkins Medical Institutions, Baltimore 21231; and Urologic Oncology Section, Surgery Branch, National Cancer Institute, Bethesda 20892 [R. E. R., J. R. G., M. L.], Maryland

In a preceding paper for brain tumors, we demonstrate a tight association between regional hypermethylation at locus D17S5 of chromosome 17p and allelic loss of this chromosome. Because 17p allelic losses occur at the earliest stages of brain tumors, the exact temporal relationship between this event and the hypermethylation could not be elucidated. In renal cancers, two linked structural changes on chromosome 17p, allelic loss and p53 gene mutations, generally occur late in progression. We now show that D17S5 hypermethylation is tightly coupled to both of these genetic changes in late stage renal tumors. However, the methylation change is the only one of the 17p abnormalities which occurs at a high incidence in early-stage renal cancers (hypermethylation, 50%; 17p allelic loss, 13%; p53 mutations, 0%). Our results firmly suggest that D17S5 regional hypermethylation precedes the appearance of the consistent 17p genetic changes in renal cancers, suggesting that this event either marks, or may even cause, chromatin changes which predispose to genetic instability.

¹ Supported by NIH Grant R01-CA43318.

² To whom requests for reprints should be addressed, at 424 N. Bond Street, Baltimore, MD 21231.

Received 3/25/93. Accepted 5/ 4/93.

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