HYPOMETHYLATION OF PERICENTROMERIC DNA IN BREAST ADENOCARCINOMAS

Drug-induced DNA demethylation in normal human cells and inherited loc alized hypomethylation in mitogen-stimulated lymphocytes from patients with a rare recessive disease (ICF: immunodeficiency, centromeric reg ion instability, facial anomalies) are associated with karyotypic inst ability. This chromosomal recombination is targeted to heterochromatin in the vicinity of the centromere (pericentromeric region) of human c hromosome I. Pericentromeric rearrangements in this chromosome as well as overall genomic hypomethylation are frequently observed in many ki nds of cancer, including breast adenocarcinoma. We found that almost h alf of 25 examined breast adenocarcinomas exhibited hypomethylation in satellite 2 DNA, which is located in the long region of heterochromat in adjacent to the centromere of chromosome I and is normally highly m ethylated. One of the 19 examined non-malignant breast tissues display ing fibrocystic changes was similarly hypomethylated in this satellite DNA. We also looked at an opposing type of methylation alteration in these cancers, namely, hypermethylation in a tumor-suppressor gene reg ion that is frequently hypermethylated in breast cancers. We found tha t increased methylation in the E-cadherin promoter region and decrease d methylation in satellite 2 DNA were often present in the same breast cancers. While hypermethylation in certain tumor-suppressor gene regi ons may favor tumorigenesis by repressing transcription, demethylation of other DNA sequences may predispose to cancer-promoting chromosomal re-arrangements. (C) 1998 Wiley-Liss, Inc.