Abstract
Up to 60% of untreated atypical hyperplastic endometrium will develop into endometrial carcinoma (EC), and for those who underwent a hysterectomy a coexisting EC is found in up to 50%. Gene promoter methylation might be related to the EC development. The aim of this study is to determine changes in gene promoter profiles in normal endometrium, atypical hyperplasia (AH) and EC in relation to K-Ras mutations. A retrospective study was conducted in patients diagnosed with endometrial hyperplasia with and without subsequent EC. Promoter methylation of APC, hMLh1, O6-MGMT, P14, P16, RASSF1, RUNX3 was analysed on pre-operative biopsies, and correlated to the final histological diagnosis, and related to the presence of K-Ras mutations. In the study cohort (n=98), differences in promoter methylation were observed for hMLH1, O6-MGMT, and P16. Promoter methylation of hMLH1 and O6-MGMT gradually increased from histologically normal endometrium to AH to EC; 27.3, 36.4% and 38.0% for hMLH1 and 8.3%, 18.2% and 31.4% for O6-MGMT, respectively. P16 promoter methylation was significantly different in AH (7.7%) compared to EC (38%). K-Ras mutations were observed in 12.1% of AH, and in 19.6% of EC cases. No association of K-Ras mutation with promoter methylation of any of the tested genes was found. In conclusion, hMLH1 and O6-MGMT promoter methylation are frequently present in AH, and thus considered to be early events in the carcinogenesis of EC, whereas P16 promoter methylation was mainly present in EC, and not in precursor lesions supporting a late event in the carcinogenesis.
Highlights
Endometrial cancer (EC) is the most common malignancy of the female genital tract in Europe and North America
Primary outcome was defined as the differences in gene promoter methylation between normal endometrium, atypical endometrial hyperplasia (AH) and endometrial carcinoma (EC) in the pre-operative samples
Secondary outcome was defined as the correlation of gene promoter methylation with the presence of K-Ras mutations and clinicopathological factors
Summary
Endometrial cancer (EC) is the most common malignancy of the female genital tract in Europe and North America. The risk of endometrial hyperplasia and progression to cancer is related to the presence of cellular atypia. The risk of developing EC when endometrial hyperplasia without atypia is present is around 3%, and increases up to 60% in atypical endometrial hyperplasia (AH). Epigenetic studies explain this risk difference by the observation of no epigenetic changes in hyperplasia without atypia, compared to multiple epigenetic changes in hyperplasia with atypia [4,5,6,7,8,9,10,11,12]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call