title: Evidence for different expression profiles for c-Met, EGFR, PTEN and the mTOR pathway in low and high grade endometrial carcinomas in a cohort of consecutive women. Occurrence of PIK3CA and K-Ras mutations and microsatellite instability.
abstract: Molecular and genetic investigations in endometrial carcinogenesis may have prognostic and therapeutic implications. We studied the expression of EGFR, c-Met, PTEN and the mTOR signalling pathway (phospho-AKT/phospho-mTOR/phospho-RPS6) in 69 consecutive tumours and 16 tissue microarrays. We also analysed PIK3CA, K-Ras mutations and microsatellite instability (MSI). We distinguished two groups: group 1 (grade 1 and 2 endometrioid cancers) and group 2 (grade 3 endometrioid and type II clear and serous cell cancers). We hypothesised that these histological groups might have different features. We found that a) survival was higher in group 1 with less aggressive tumours (P⟨0.03); b) EGFR (P=0.01), PTEN and the AKT/mTOR/RPS6 signalling pathway were increased in group 1 versus group 2 (P=0.05 for phospho-mTOR); c) conversely, c-Met was higher (P⟨0.03) in group 2 than in group 1; d) In group 1, EGFR was correlated with c-Met, phospho-mTOR, phospho-RPS6 and the global activity of the phospho-AKT/phospho-mTOR/phospho-RPS6 pathway. In group 2, EGFR was correlated only with the phospho-AKT/phospho-mTOR/phospho-RPS6 pathway, whereas c-Met was correlated with PTEN; e) survival was higher for tumours with more than 50% PTEN-positive cells; f) K-RAS and PIK3CA mutations occurred in 10-12% of the available tumours and MSI in 40.4%, with a loss of MLH1 and PMS2 expression. Our results for endometrial cancers provide the first evidence for a difference in status between groups 1 and 2. The patients may benefit from different targeted treatments, anti-EGFR agents and rapamycin derivatives (anti-mTOR) for group 1 and an anti c-MET/ligand complex for group 2.
authors.affiliation: Department of Pathology, and Department of Gynaecology, Hôpital Bichat-Claude Bernard, Paris.
authors.forename: Anne
authors.initials: A
authors.lastname: Thoury
authors.affiliation: Department of Pathology, Hôpital Bichat-Claude Bernard, Paris.
authors.forename: Véronique
authors.initials: V
authors.lastname: Descatoire
authors.affiliation: Institut de la Santé et de la Recherche Médicale (INSERM U773) CRB3, Paris, France.
authors.forename: Larissa
authors.initials: L
authors.lastname: Kotelevets
authors.affiliation: Department of Molecular Biology, Hôpital Bichat-Claude Bernard, Paris.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.affiliation: Department of Molecular Biology, Hôpital Bichat-Claude Bernard, Paris.
authors.forename: Guylène
authors.initials: G
authors.lastname: Bertrand
authors.affiliation: Department of Molecular Biology, Hôpital Bichat-Claude Bernard, Paris.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Theou-Anton
authors.affiliation: Department of Gynaecology, Hôpital Bichat-Claude Bernard, Paris.
authors.forename: Caroline
authors.initials: C
authors.lastname: Frey
authors.affiliation: Department of Pathology, Hôpital Bichat-Claude Bernard, Paris.
authors.forename: Catherine
authors.initials: C
authors.lastname: Genestie
authors.affiliation: Department of Oncology, Hôpital Beaujon, Clichy, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.affiliation: Institut de la Santé et de la Recherche Médicale (INSERM U773) CRB3, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chastre
authors.affiliation: Institut de la Santé et de la Recherche Médicale (INSERM U773) CRB3, Paris, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Lehy
authors.affiliation: Department of Pathology, Hôpital Bichat-Claude Bernard, and Institut de la Santé et de la Recherche Médicale (INSERM U773) CRB3, Paris, France. francine.walker@bch.aphp.fr.
authors.forename: Francine
authors.initials: F
authors.lastname: Walker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008024:Ligands; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012189:Retrospective Studies; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019394:Ki-67 Antigen; D008024:Ligands; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C494929:PTEN protein, human