Biomarkers of endometrial cancer and related gynaecological malignancies

Abstract

In the Western World, endometrial cancer is the most common malignancy of the female genital tract. Endometrioid endometrial carcinoma (EEC or Type I tumour), accounts for approximately 75% of cases. Type II tumours, of which uterine papillary serous carcinoma (UPSC) is the most common subtype, are less common. Since classification as EEC or UPSC has therapeutic and prognostic implications, it is important to make the proper diagnosis. UPSC share their aggressive clinical behaviour and their histological appearance with serous carcinoma of the Fallopian tube and ovary. In this thesis genetic and epigenetic modifications in endometrial cancer and related gynaecological malignancies were studied to gain a better insight in its molecular pathogenesis, and to identify possible diagnostic and prognostic markers. A developing solid tumour will outgrow its own vasculature beyond the size of several cubic millimetres, resulting in hypoxia. Hypoxia has been found to be an important event in carcinogenesis as it renders a more aggressive phenotype. Hypoxia inducible factor 1 (HIF-1) is the key cellular survival protein during hypoxia. HIF-1? expression might be helpful to identify patients who are at risk of developing recurrent disease. Perinecrotic HIF-1? expression (thought to be hypoxia driven) appeared to be an independent indicator of poor prognosis in EEC. More aggressive adjuvant treatment might be necessary to improve the outcome of these patients. To this end, HIF-1? itself can be an attractive therapeutic target. Claudins have recently been identified as a 24-gene family of structures and functional components of the tight junctions in epithelial and endothelial cells. Claudins show a tissue-specific expression pattern in humans and diversity in the expression patterns between normal tissue and its corresponding tumour. We found aberrant (i.e. not in the membranes) nuclear claudin 3 expression to be a typical feature of UPSC. In 80% of cases nuclear claudin 3 was seen in UPSC, compared to only 17% of EEC, 3% of OVCA and none of FTC. Promoter methylation is an epigenetic event that plays an important role in carcinogenesis by downregulation of tumour suppressor gene (TSG) expression. We show that promoter methylation was more frequent in EEC than in UPSC. Methylation of CDH13, MLH1 and TIMP3 was typical for EEC, while CDKN2B and TP73 methylation characterised UPSC. The correct tumour type could be predicted in almost 90% of EEC and 70% of UPSC with this TSG panel. However, this tumour type specific methylation pattern is not yet sufficiently differentiating to be of clinical use. Comparing the methylation status of TSGs in the different serous tumours showed that RASSF1(A) methylation was typical for endometrial origin. GSTP1 on the other hand was more frequently methylated in OVCA and FTC. As UPSC exhibit different genetic- and epigenetic profiles compared to serous ovarian- and Fallopian tube carcinoma, it should be regarded as distinct entity. All in all, especially promoter methylation seems a promising biomarker in endometrial cancer. The identification of such markers is an important step for individualised patient tailored therapy and, ultimately, in improving patient outcomes.