title: FGFR2 alterations in endometrial carcinoma.
abstract: 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 FGFR2 have 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. FGFR2 mutations 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 FGFR2 in 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 FGFR2 gene were detected in exons 6 and 11 (S252W and N549K, respectively; 6.45%). Results support the hypothesis that FGFR2 has 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.
authors: Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Lleida, Spain.
authors: Sonia
authors: S
authors: Gatius
authors: Ana
authors: A
authors: Velasco
authors: Ainara
authors: A
authors: Azueta
authors: Maria
authors: M
authors: Santacana
authors: Judit
authors: J
authors: Pallares
authors: Joan
authors: J
authors: Valls
authors: Xavier
authors: X
authors: Dolcet
authors: Jaime
authors: J
authors: Prat
authors: Xavier
authors: X
authors: Matias-Guiu
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002277:Carcinoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000032:analysis; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D004717:Endometrium / Q000737:chemistry* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008565:Membrane Proteins; D008597:Menstrual Cycle; D020125:Mutation, Missense; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000032:analysis; D016133:Polymerase Chain Reaction; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000032:analysis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000032:analysis; D013030:Spain; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D008565:Membrane Proteins; C411762:RASSF1 protein, human; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C485561:SPRY2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human