HOMOZYGOUS DELETION, REARRANGEMENT AND HYPERMETHYLATION IMPLICATE CHROMOSOME REGION 3P14.3-3P21.3 IN SPORADIC BREAST-CANCER DEVELOPMENT

DNAs from 19 malignant human breast tumors and 2 benign fibroadenomas were analyzed for heterozygosity at 5 polymorphic loci on the short arm of chromosome 3. One homozygous deletion and one rearrangement were identified using probe D3S2 which maps to 3pI4.3-3p2I.I. This probe also detected novel hybridizing fragments of 2.0 kb and/or 3.4 kb in 6/18 (33%) of the malignant tumor samples that hybridized with the D3S2 probe following digestion with the 5'-methylcytosine-insensitive enzyme Mspl. Comparisons of Hpall and Mspl digestion showed that all but one of the tumor DNAs analyzed were hypermethylated. The two fibroadenoma DNAs were not as highly methylated and had hybridizing fragments of 3.4 kb after Hpall digestion. These malignant breast-tumor DNAs exhibit 3 mechanisms by which a tumor-suppressor gene hypothesized to reside at 3pI4-3p2I could be inactivated: homozygous deletion, rearrangement and hypermethylation, and strongly implicate this 3p chromosome region in breast-tumor development. (C) 1994 Wiley-Liss, Inc.