DNA hypomethylation and chromosomal rearrangements in the ICF syndrome and in cancer

Overrepresentation of chromosomal aberrations targeted to the pericentromeric region of chromosomes 1 and 16 is frequently detected in different types of cancers. Similar chromosomal anomalies are always found in mitogen-stimulated lymphocytes in the ICF syndrome (i&barbelow;mmunodeficiency, c&barbelow;entromeric region instability, and f&barbelow;acial anomalies), and are a diagnostic feature of this unique, inherited DNA methylation immunodeficiency disease involving loss of DNA methyl transferase 3B activity. Our research has demonstrated that almost half of the examined breast adenocarcinomas, Wilms tumors and majority of ovarian epithelial cancers exhibit hypomethylation of satellite 2 DNA which is located in the long region of heterochromatin of chromosome 1, adjacent to the centromere. The principal centromeric DNA component, satellite a DNA, was found to be highly hypomethylated in majority of the Wilms tumors and malignant ovarian epithelial tumors. As in the ICF syndrome where constitutive hypomethylation of the juxtacentromeric heterochromatin of chromosomes 1 and 16 has been shown in lymphocytes, extensive abnormal hypomethylation of these normally highly methylated sequences may predispose to the development of the rearrangements which are characteristic for ICF as well as which favor oncogenesis. We have also shown that lymphoblastoid cell lines (LCLs) established from ICF patients recapitulate and continuously generate the same types of targeted chromosomal aberrations found in mitogen-stimulated lymphocytes. These LCLs maintain the abnormal hypomethylation in the juxtacentromeric regions of chromosomes 1 and 16 seen in the ICF tissues. In addition to improving the understanding of the mechanism of generation of these rearrangements, we have also demonstrated for the first time that ICF LCLs are extremely hypersensitive to ionizing radiation. Prolonged cell cycle arrest, increased apoptotic cell death and greatly enhanced non-apoptotic cell death contribute to the hypersensitivity to γ rays. No deficiencies in cell cycle checkpoints were found in ICF LCLs, nor was there hypersensitivity to radiation-induced chromosome breakage. We hypothesize that ICF-associated undermethylation of some regulatory gene (s) leads to an exaggerated response to radiation-induced breaks in DNA yielding heightened rates of cell death an irreversible cell cycle arrest. Cancer-linked DNA hypomethylation might result in similar outcomes during carcinogenesis.