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Carcinogenesis Advance Access first published online on January 27, 2005
This version published online on January 27, 2005
Carcinogenesis, doi:10.1093/carcin/bgi011
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Oxford University Press
Received August 17, 2004
Revised December 16, 2004
Accepted December 18, 2004

CARCINOGENESIS

Epigenetic and genetic alterations of p33ING1b in ovarian cancer

Dan-Hua Shen 1, Kelvin Yuen-Kwong Chan 2, Ui-Soon Khoo 3, Hextan Yuen-Sheung Ngan 4, Wei-Cheng Xue 3, Pui-Man Chiu 3, Philip Ip 3, and Annie Nga-Yin Cheung 3*

1 Department of Pathology, People's Hospital, Peking University, Beijing
2 Department of Pathology, Hong Kong Jockey Club Clinical Research Centre, The University of Hong Kong, Hong Kong, China; Department of Obstetrics and Gynecology, Hong Kong Jockey Club Clinical Research Centre, The University of Hong Kong, Hong Kong, China
3 Department of Pathology, Hong Kong Jockey Club Clinical Research Centre, The University of Hong Kong, Hong Kong, China
4 Department of Obstetrics and Gynecology, Hong Kong Jockey Club Clinical Research Centre, The University of Hong Kong, Hong Kong, China

* To whom correspondence should be addressed.
Annie Nga-Yin Cheung, E-mail: anycheun{at}hkucc.hku.hk


  Abstract

p33ING1b is a candidate tumor suppressor gene and is a nuclear protein. We investigated whether genetic and epigenetic mechanisms may effect p33ING1b expression in ovarian cancer thus contributing towards its pathogenesis. A total of 111 ovarian cancers collected from Beijing and Hong Kong were used for this study. Weak or negative p33ING1b protein expression was demonstrated by immunohistochemistry on tissue microarray in 28/111 cases. Real-time quantitative RT-PCR also showed overall significant reduction of p33ING1b mRNA expression (p=0.0137), with 53.1% (17/32) cases showing 2 to 5-fold reduction and absence of expression. The reduction of mRNA expression in cancer correlated with decreased p33ING1b protein expression (p<0.0001). Whilst no p33ING1b mutation was found, allelic loss at the p33ING1b locus was demonstrated in 25% (8/32) cases. The allelic loss profiles also showed statistical significant correlation with reduction of p33ING1b protein and mRNA expression (p=0.031 and 0.030). Promoter methylation as assessed by methylation specific PCR was found in 23.9% (21/88) cases analyzed. Bisulfite sequencing results confirmed the p33ING1b promoter methylation status of these methylation positive cases. Statistical significant correlation between methylation and mRNA expression (p=0.006) was demonstrated. Treatment with demethylating drug, 5'-aza-2'-deoxycytidine, resulted in dosage dependent elevated mRNA expression of p33ING1b in ovarian cancer cell lines. This is first study reporting epigenetic mechanism regulating p33ING1b expression. Our findings support that genetic and epigenetic alteration of p33ING1b are likely to contribute towards the pathogenesis of ovarian cancers.

Keywords: promoter methylation; expression of p33ING1b; epigenetic and genetic alteration; tissue microarray; ovarian cancer.
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