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. ' 2005 Wiley-Liss, Inc.Key words: BRAF; K-ras; CDKN2A (p16); endometrial cancer; prognosis Several pathways have been implicated in the pathogenesis of endometrial carcinoma. 1 Ras mutations are common in human cancers and have previously been found in 14% within the present population-based patient series. 2 Recently, it has been reported that mutations of BRAF provide an alternative route for activation of the RAS-mediated MAP-kinase signalling pathway. Mutations in BRAF have been reported in melanomas, colorectal cancers and ovarian tumours. 3,4 These mutations of BRAF have also been linked to microsatellite instability (MSI) in colorectal carcinoma. 5 We wanted to investigate the frequency of BRAF mutations in endometrial cancer and in particular their relation to MSI and Ras mutations, especially since mutations in Ras are relatively few in this group of tumours.As evidenced from studies on melanoma, the mutations in the BRAF gene, though early, are not sufficient for tumour formation, for which an additional genetic hit is required. This is supported by characterization of overlapping BRAF mutations and CDKN2A aberrations in melanomas 6 and also occurrence of a high frequency of BRAF mutations in tumours from families with germline...

Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats

“…Loss of P16 expression has been found more commonly in human serous (type II, about 45%) compared with endometrioid carcinomas (type I, less than 10% and mainly found in high-grade tumors; Salvesen et al 2000). P16 inactivation correlates with K-RAS mutations, high stage and high grading of tumors as well as poor survival (Salvesen et al 2005). We found significant low expression level (28-fold) of P16 in the EAC tumors, which is in accordance to result from a recent study indicating frequent hemi-or homozygous deletions of P16 in BDII rat EAC tumors ).…”

Analysis of a correlation between the BRAF V600E mutation and abnormal DNA mismatch repair in patients with sporadic endometrial cancer

“…In contrast, Salvesen et al found the activating BRAF V600E mutation in only 2% of cases of endometrial cancer, and a consensus has not been obtained regarding the correlation between carcinogenesis of endometrial cancer and BRAF mutation (13). In our analysis, no BRAF V600E mutation was observed in cases of sporadic endometrial cancer.…”

“…Feng et al found BRAF mutations in 21% of patients with endometrial cancer and suggested that the mutation correlated with decreased hMLH1 expression (12). However, Salvesen et al found a BRAF mutation in only 2% of patients with endometrial cancer (13). Therefore, it is unclear whether mutation of BRAF is important in carcinogenesis of endometrial cancer and whether the mutation may be linked to abnormal expression of the hMLH1 gene.…”

PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters

“…[9][10][11] In contrast, the frequency of B-RAF mutations is significantly lower. [43][44][45] It has been suggested that PIK3CA and K-RAS mutations are mutually exclusive alterations. 27 However, in our study, K-RAS mutations were detected in 17% of cases and coexisted with PIK3CA mutations in 4%.…”