title: Low frequency of BRAF and CDKN2A mutations in endometrial cancer.
abstract: Several pathways have been implicated in the pathogenesis of endometrial carcinoma. Based on recent reports, BRAF mutations provide an alternative route for activation of the RAS signalling pathway. The CDKN2A (p16) tumour suppressor gene is also altered in several tumour types. We therefore wanted to assess the pattern and prognostic impact of BRAF mutations and p16 alterations in endometrial carcinomas. Only 1 of 48 tumours (2%) was found to have a BRAF mutation in exon 15, whereas 8 of 45 tumours (18%) had a K-ras mutation. Homozygous deletion, amplification, promoter region methylation or mutation of the p16 gene was seen in 6 cases (13%), and 18 cases (38%) carried polymorphisms in the p16 gene. All tumours with presence of p16 methylation, non-sense mutation, deletion or amplification exhibited loss of p16 expression as evaluated by immunohistochemistry. Presence of a p16 hit was significantly correlated with high FIGO stage (p = 0.04), high histologic grade (p = 0.02), estrogen receptor negativity (p = 0.05), pathologic expression of p53 (p = 0.02), pathologic expression of p16 (p = 0.05) and poor survival (p = 0.02). There was also a significant correlation between loss of p16 expression and K-ras mutations, pathologic p53 expression and serous papillary/clear cell histologic types (p = 0.05/p = 0.001/p = 0.002). In conclusion, BRAF mutation is an infrequent finding in endometrial carcinomas. Loss of p16 expression is seen in all cases with alterations of the p16 gene. The presence of a p16 hit might be important in a subset of endometrial carcinomas with aggressive clinical behaviour. However, the mechanism of p16 inactivation remains unclear for the majority of cases exhibiting loss of expression, but the interactions with K-ras and p53 should be further studied.
authors.affiliation: Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway. helga.salvesen@gades.uib.no
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Ingunn
authors.initials: I
authors.lastname: Stefansson
authors.forename: Sabrina
authors.initials: S
authors.lastname: Angelini
authors.forename: Nicola
authors.initials: N
authors.lastname: MacDonald
authors.forename: Johanna
authors.initials: J
authors.lastname: Smeds
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
mesh_terms: D000368:Aged; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D019942:Genes, p16; D011905:Genes, ras; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf