DNA hypermethylation, Her-2/neu overexpression and p53 mutations in ovarian carcinoma.
OBJECTIVE
To define patterns of aberrant DNA methylation, p53 mutation and Her-2/neu overexpression in tissues from benign (n=29), malignant (n=100), and border line malignant ovaries (n=10), as compared to normal (n=68) ovarian tissues. Further, to explore the relationship between the presence of genetic and epigenetic abnormalities in ovarian cancers, and assess the association between epigenetic changes and clinical stage of malignancy at presentation and response to therapy.


METHODS
The methylation status of 23 genes that were previously reported associated with various epithelial malignancies was assessed in normal and abnormal ovarian tissues by methylation-specific PCR. The presence of p53 mutation (n=82 cases) and Her-2/neu overexpression (n=51 cases) were assessed by DNA sequencing and immunohistochemistry, respectively.


RESULTS
Methylation of four genes (MINT31, HIC1, RASSF1, and CABIN1) was significantly associated with ovarian cancer but not other ovarian pathology. Her-2/neu overexpression was associated with aberrant methylation of three genes (MINT31, RASSF1, and CDH13), although aberrant methylation was not associated with p53 mutations. Methylation of RASSF1 and HIC1 was more frequent in early compared to late stage ovarian cancer, while methylation of CABIN1 and RASSF1 was associated with response to chemotherapy.


CONCLUSIONS
DNA methylation of tumor suppressor genes is a frequent event in ovarian cancer, and in some cases is associated with Her-2/neu overexpression. Methylation of CABIN1 and RASSF1 may have the utility to predict response to therapy.
Feng
Qinghua
Q
Department of Pathology, School of Medicine, University of Washington, Seattle, Washington, USA.
Deftereos
Georgios
G
Hawes
Stephen E
SE
Stern
Joshua E
JE
Willner
Julia B
JB
Swisher
Elizabeth M
EM
Xi
Longfu
L
Drescher
Charles
C
Urban
Nicole
N
Kiviat
Nancy
N