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Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes such as embryogenesis, adult tissue homeostasis and cell proliferation. Mutations in FGFR2have been reported in up to 10–12% of endometrial carcinomas identical to those found in congenital craniofacial disorders. Inhibition of FGFR2 could be a new therapeutic target in endometrial carcinoma. FGFR2 immunostaining was assessed in three tissue microarrays: one constructed from paraffin-embedded blocks of 60 samples of normal endometrium in different phases of menstrual cycle, and two tissue microarrays containing endometrial carcinoma samples (95 and 62 cases). FGFR2 expression was correlated with stage, histological type and grade as well as with immunostaining of PTEN, RASSF1A, estrogen and progesterone receptors, KI67, Cyclin D1, STAT-3 and SPRY2. FGFR2mutations were assessed by PCR and direct sequencing, with DNA obtained from 31 paraffin-embedded endometrial carcinoma samples. In normal endometrium, FGFR2 expression was higher in the secretory than in the proliferative phase (P=0.001), with an inverse correlation with Ki67 (P=0.00032), suggesting a tumor-suppressor role for FGFR2in normal endometrium. Cytoplasmic expression of FGFR2 was higher in endometrial carcinoma when compared with the atrophic endometrium from the same patients (P=0.0283), but was lower in comparison with normal endometrium from women in the menstrual cycle. Interestingly, nuclear staining was observed in some cases, and it was less frequent in endometrial carcinoma when compared with the adjacent atrophic endometrium (P=0.0465). There were no statistical differences when comparing superficial and myoinvasive endometrial carcinoma samples. Endometrioid endometrial carcinomas showed higher expression of FGFR2 than nonendometrioid endometrial carcinomas (fold change 2.56; P=0.0015). Grade III endometrioid endometrial carcinomas showed decreased FGFR2 expression when compared with grade II endometrioid endometrial carcinomas (P=0.0055). No differences were found regarding pathological stage. Two missense mutations of FGFR2gene were detected in exons 6 and 11 (S252W and N549K, respectively; 6.45%). Results support the hypothesis that FGFR2has a dual role in the endometrium, by inhibiting cell proliferation in normal endometrium during the menstrual cycle, but acting as an oncogene in endometrial carcinoma.

Alterations in the regulation of the RAS–MAPK pathway are frequent in endometrial carcinoma. RASSF1Ais a tumor-suppressor gene that can regulate this pathway negatively. RASSF1Ahas been found to be inactivated by promoter methylation in some human tumors. The aim of the study was to assess the immunohistochemical expression of RASSF1Ain normal endometrium and endometrial carcinoma, and to correlate its expression with K-RASmutations, presence of microsatellite instability, RASSF1Apromoter methylation, and clinicopathological data. RASSF1A immunostaining was evaluated in one tissue microarray constructed from 80 paraffin-embedded samples of normal endometrium, and two tissue microarrays constructed with a total of 157 endometrial carcinomas (one constructed with 95 endometrial carcinomas previously evaluated for K-RASmutations, and microsatellite instability, and another one containing 62 endometrial carcinomas that were also subjected to RASSF1Apromoter methylation analysis). RASSF1A immunostaining was correlated with cell proliferation (Ki67), Cyclin D1expression and clinicopathological data. Promoter methylation of RASSF1Awas assessed by methylation-specific PCR. RASSF1A immunostaining was variable during the menstrual cycle in normal endometrium. RASSF1A expression was significantly reduced in 48% of endometrial carcinomas, particularly in tumors exhibiting microsatellite instability. RASSF1A-promoter methylation was very frequent in endometrial carcinoma (74%), and was frequently associated with reduced expression of RASSF1A. RASSF1A-promoter hypermethylation was common in advanced-stage endometrial carcinoma. The results suggest that reduced expression of RASSF1Amay play a role in endometrial carcinogenesis by controlling cell proliferation and apoptosis through the MAPK-signaling pathway.