Background: Mutational activation of KRAS and BRAF proto-oncogenes contributes to the development of many human cancers. Current research on gynecological cancer and specifically in cervical and endometrial cancer is focused on the mechanisms of their mutational activation.
Objectives: In view of the paucity of data on their mutation frequency and the status of BRAF in these two types of gynecological cancer, we performed a systematic molecular study in 114 clinically and histologically well-defined malignant tumors of uterine cervix and endometrium and correlated the mutation status of KRAS and BRAF with the age at diagnosis and with tumor grade, stage or histological type.
Methods: Direct sequence analysis of the PCR products of KRAS and BRAF genes was used to screen for known activating mutations.
Results: In 67 cases of endometrial cancer, six KRAS mutations (8.9%) were found, four at codon 12 (5.9%) and two at codon 13 (2.9%), while no mutation was detected at codon 61. Most of the mutations occurred in surgical stage I and in the endometrioid adenocarcinoma subtype. We also detected three KRAS point mutations (6.3%) in the 47 cervical cancer samples, two at codon 12 (4.2%) and one at codon 13 (2.1%), while there was no mutation at codon 61. On the contrary, no mutation was identified in BRAF exon 15 for either endometrial or cervical cancer samples at position V600, which represents the most frequently mutated site of BRAF in human cancer. There was no association between KRAS mutations with either histological type, tumor grade or stage. Interestingly, however, KRAS mutation status in endometrial cancer was strongly associated with increased age at diagnosis (P < 0.001).
Conclusions: Our data document (a) the absence of BRAF mutations in cervical and endometrial cancer, despite the mutation status of KRAS, (b) suggest that KRAS mutations reflect an early event in endometrial carcinogenesis and (c) imply that BRAF activation is involving alternative pathways in these two types of cancer.