Hypomethylation of pericentromeric DNA in breast adenocarcinomas

Abstract

Drug‐induced DNA demethylation in normal human cells and inherited localized hypomethylation in mitogen‐stimulated lymphocytes from patients with a rare recessive disease (ICF: i―mmunodeficiency, c―entromeric region instability, f―acial anomalies) are associated with karyotypic instability. This chromosomal recombination is targeted to heterochromatin in the vicinity of the centromere (pericentromeric region) of human chromosome 1. Pericentromeric rearrangements in this chromosome as well as overall genomic hypomethylation are frequently observed in many kinds of cancer, including breast adenocarcinoma. We found that almost half of 25 examined breast adenocarcinomas exhibited hypomethylation in satellite 2 DNA, which is located in the long region of heterochromatin adjacent to the centromere of chromosome 1 and is normally highly methylated. One of the 19 examined non‐malignant breast tissues displaying 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 region that is frequently hypermethylated in breast cancers. We found that increased methylation in the E‐cadherin promoter region and decreased methylation in satellite 2 DNA were often present in the same breast cancers. While hypermethylation in certain tumor‐suppressor gene regions may favor tumorigenesis by repressing transcription, demethylation of other DNA sequences may predispose to cancer‐promoting chromosomal re‐arrangements. Int. J. Cancer 77:833–838, 1998. © 1998 Wiley‐Liss, Inc.

Demethylation of MAGE promoters during gastric cancer progression

“…Global DNA hypomethylation is thought to occur during the early stages of tumour development in gastric and other tissues (Goelz et al, 1985;Narayan et al, 1998;Lin et al, 2001;Bariol et al, 2003). Additionally, in pulmonary carcinogenesis, demethylation of the promoter CpG islands of MAGE genes has been observed not only in tumours but also in the adjacent non-neoplastic lung tissues and bronchial epithelia from smokers .…”

“…Global DNA hypomethylation has been observed in carcinomas of the breast, liver, and colon, and is considered to occur in the early stages of tumour development (Goelz et al, 1985;Cravo et al, 1996;Narayan et al, 1998;Lin et al, 2001;Bariol et al, 2003). However, little is known about promoter hypomethylation of specific genes such as oncogenes and growth-related genes, with the exception of the association between demethylation and increased expression of c-abl, c-myc, Ha-ras, and raf (Cheah et al, 1984;Weitzman et al, 1989;Sharrad et al, 1992;Counts and Goodman, 1994).…”

Hypomethylation of Chromosome 1 Heterochromatin DNA Correlates with q-Arm Copy Gain in Human Hepatocellular Carcinoma

“…19 Two g of DNA were digested in 20 U of CpG methylsensitive restriction enzyme BstBI (New England Biolabs, Beverly, MA) for 16 hours. Complete DNA digestion was indicated with the aid of an internal DNA control, HindIII.…”

DNA hypomethylation is prevalent even in low-grade breast cancers

“…8,9 By Southern blot analysis with a CpG methylation-sensitive restriction endonuclease, we have shown that satellite 2 DNA (Sat2), the main sequence in the long juxtacentromeric (centromere-adjacent) heterochromatin of chromosome 1 (Chr1), is often hypomethylated in breast adenocarcinomas and Wilms tumors as well as in ovarian epithelial carcinomas. [10][11][12] Hypomethylation of this satellite DNA at 1qh was strongly linked to hypomethylation of the highly homologous satellite DNA at 16qh (Chrl6 Sat2) in these three disparate types of cancer. Also, in human hepatocellular carcinomas, hypomethylation of Sat2 was highly concordant with that of Sat3, the main DNA component of the long juxtacentromeric heterochromatin of Chr9.…”