Abstract:
:Hypermethylation at certain CpG-rich promoters and hypomethylation at repeated DNA sequences are very frequently found in cancers. We provide the first report that a DNA sequence (NBL2) can be either extensively hypermethylated or hypomethylated in cancer. Previously, it was shown that NBL2, a complex tandem DNA repeat in the acrocentric chromosomes, is hypomethylated at NotI sites in >70% of neuroblastomas and hepatocellular carcinomas and in cells from ICF syndrome (DNMT3B-deficiency) patients. Unexpectedly, by Southern blot analysis of 18 ovarian carcinomas, 51 Wilms tumors, and various somatic control tissues, we found that >70% of the cancers exhibited large increases in methylation at HhaI sites in NBL2 compared with all the controls. In contrast, 17% of the carcinomas showed major decreases in methylation at HhaI and NotI sites. The intermediate levels of methylation at HhaI sites in somatic controls enabled this discovery of cancer-linked hypermethylation and hypomethylation in NBL2. In a comparison of ovarian epithelial carcinomas, low malignant potential tumors, and cystadenomas, NBL2 hypermethylation at HhaI sites was significantly related to the degree of malignancy, and hypomethylation was seen only in the carcinomas. By RT-PCR, we found NBL2 transcripts at low levels in a few cancers and undetectable in various normal tissues. In the tumors there was no association of NBL2 hypomethylation and transcription, but this may reflect NBL2's lack of identifiable promoter elements and our evidence for run-through transcription from adjacent sequences into NBL2. The propensity of NBL2 sequences to become either hypermethylated or hypomethylated in cancer suggests that these opposite epigenetic changes share an early step during carcinogenesis and that cancer-linked hypermethylation might be spontaneously reversible.
journal_name
Cancer Biol Therjournal_title
Cancer biology & therapyauthors
Nishiyama R,Qi L,Tsumagari K,Weissbecker K,Dubeau L,Champagne M,Sikka S,Nagai H,Ehrlich Mdoi
10.4161/cbt.4.4.1622keywords:
subject
Has Abstractpub_date
2005-04-01 00:00:00pages
440-8issue
4eissn
1538-4047issn
1555-8576pii
1622journal_volume
4pub_type
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