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Open Access Highly Accessed Research article

Differential DNA methylation profiles in gynecological cancers and correlation with clinico-pathological data

Hui-Juan Yang1, Vincent WS Liu2*, Yue Wang3, Percy CK Tsang2 and Hextan YS Ngan2

Author Affiliations

1 Department of Gynecologic Oncology, Fudan University Cancer Hospital, Shanghai, China

2 Department of Obstetrics & Gynecology, University of Hong Kong, Hong Kong SAR, China

3 Department of Obstetrics & Gynecology, People's Hospital, Peking University, China

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BMC Cancer 2006, 6:212  doi:10.1186/1471-2407-6-212

Published: 23 August 2006

Abstract

Background

Epigenetic gene silencing is one of the major causes of carcinogenesis. Its widespread occurrence in cancer genome could inactivate many cellular pathways including DNA repair, cell cycle control, apoptosis, cell adherence, and detoxification. The abnormal promoter methylation might be a potential molecular marker for cancer management.

Methods

For rapid identification of potential targets for aberrant methylation in gynecological cancers, methylation status of the CpG islands of 34 genes was determined using pooled DNA approach and methylation-specific PCR. Pooled DNA mixture from each cancer type (50 cervical cancers, 50 endometrial cancers and 50 ovarian cancers) was made to form three test samples. The corresponding normal DNA from the patients of each cancer type was also pooled to form the other three control samples. Methylated alleles detected in tumors, but not in normal controls, were indicative of aberrant methylation in tumors. Having identified potential markers, frequencies of methylation were further analyzed in individual samples. Markers identified are used to correlate with clinico-pathological data of tumors using χ2 or Fisher's exact test.

Results

APC and p16 were hypermethylated across the three cancers. MINT31 and PTEN were hypermethylated in cervical and ovarian cancers. Specific methylation was found in cervical cancer (including CDH1, DAPK, MGMT and MINT2), endometrial cancer (CASP8, CDH13, hMLH1 and p73), and ovarian cancer (BRCA1, p14, p15, RIZ1 and TMS1). The frequencies of occurrence of hypermethylation in 4 candidate genes in individual samples of each cancer type (DAPK, MGMT, p16 and PTEN in 127 cervical cancers; APC, CDH13, hMLH1 and p16 in 60 endometrial cancers; and BRCA1, p14, p16 and PTEN in 49 ovarian cancers) were examined for further confirmation. Incidence varied among different genes and in different cancer types ranging from the lowest 8.2% (PTEN in ovarian cancer) to the highest 56.7% (DAPK in cervical cancer). Aberrant methylation for some genes (BRCA1, DAPK, hMLH1, MGMT, p14, p16, and PTEN) was also associated with clinico-pathological data.

Conclusion

Thus, differential methylation profiles occur in the three types of gynecologic cancer. Detection of methylation for critical loci is potentially useful as epigenetic markers in tumor classification. More studies using a much larger sample size are needed to define the potential role of DNA methylation as marker for cancer management.