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From the Institute of Pathology, Medizinische Hochschule Hannover,Hannover, Germany
The aberrant methylation of cytosine residues in the promoter
region of growth regulatory genes is now widely recognized as an
additional mechanism for gene inactivation in cancer cells. In this
study we analyzed the methylation status of four growth regulatory
genes (p16, RASSF1A, cyclinD2,
14-3-3
) during breast cancer progression. For this purpose
invasive and noninvasive tumor cell populations as well as hyperplastic
cell proliferations were isolated from a series of archival breast
tissue specimens (n = 57) using laser-assisted
microdissection. A new real-time polymerase chain reaction-based assay
was used for the sensitive and quantitative determination of the
cell-specific methylation status. We found that aberrant promoter
methylation was already prevalent in pure intraductal carcinoma with
different frequencies and different methylation levels for the four
genes analyzed. For RASSF1A and 14-3-3
promoter methylation was also demonstrated in epithelial hyperplasia
and intraductal papillomas. By contrast, aberrant methylation
of cyclinD2 and p16 was restricted to
cancerous epithelium. Increased methylation of the
cyclinD2 gene was significantly associated with a higher
van Nuys grade. Furthermore, when intraductal and invasive
tumor cells were compared, significant quantitative changes in
the methylation level were detected primarily within the
cyclinD2 gene. These results demonstrate that promoter
methylation is an early and frequent event in breast cancer
development, but displays great quantitative and gene-specific
differences, and changes in a gene-specific manner during tumor
progression.
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