More than of the BRAF

More than 90% of the BRAF mutations in human malignantmelanomas involve hematoxylin 600, and 80% of these mutations are comprised of the V600E mutation. Nevertheless, V600K is the second most common mutation, constituting 14–28% of the BRAF mutations that underlie melanoma (Forschner et al., 2013). From one recent study, three novel mutations in exon 11 of BRAF—G442S, W450Stop and I457T—have been identified in melanoma (acral and mucosal) in addition to the eight previously reported mutations in exon 11 and 15: G466R, D594E, D594G, V600E, V600K, K601E, W604Stop and S616F (Si et al., 1990).
From the literature, the BRAF protein has three AKT phosphorylation sites: Thr439, Ser428 and Ser364. In vitro substitution of the Thr439 residue with an Ala residue leads to BRAF activation through the loss of AKT-induced inhibition of RAF1 phosphorylation. Hence, the detection of K438T and K438Q in melanoma, similar to Thr439, is likely to inhibit AKT-dependent phosphorylation (Brose et al., 2002). Similarly, the presence of Ser428, Ser364 and the aforementioned novel mutations (G442S, W450Stop and I457T) (Si et al., 1990) in the vicinity of Thr439 are suggested to play a role in tumourigenesis (Brose et al., 2002).

During the past few years, patients with epithelial ovarian cancer have been treated identically in clinical trials and in pathological practise (Gershenson, 2013). The development of a 2-tier system for serous carcinomas, with low and high grades, is now generally accepted (Kohn and Hurteau, 2013). This simple approach, which is based on biological evidence, proposes that both tumours develop through different pathways. With infrequent mitotic figures, low-grade serous carcinomas, such as invasive micropapillary serous carcinoma (MPSC), show low-grade nuclei and are believed to evolve from adenofibromas or cystadenomas, which are borderline in the tumour-serous carcinoma sequence, via mutation in the KRAS, BRAF, or ERBB2 genes (Vang et al., 2009). Mutations in the KRAS, BRAF, or ERBB2 genes result in the upregulation of MAPK, which in turn regulates uncontrolled proliferation in atypical proliferative serous tumours (APST). Serous cystadenomas found adjacent to APSTs have been found to have identical KRAS or BRAF mutations, suggesting that the presence of APSTs near the cystadenomas may support the regulation of serous carcinomas (Vang et al., 2009).
While BRAF V600E has been reported to be prevalent in 33% of tumours in the past, recent findings exhibited only 2% low-grade serous mutations (Ziai and Hui, 2012). Conversely, in low-grade ovarian serous carcinoma patients, the correlation between BRAF and KRAS has not yet been explored. Additionally, unlike previous findings, one report discussed the low frequency characterisation of KRAS and BRAF mutations in advanced stage low-grade serous carcinomas (Wong et al., 2010). Recently, 20–40% of low-grade serous carcinomas have been characterised with KRAS mutations, while BRAF mutations are found in approximately 5% of this subtype (Gershenson, 2013). In the literature, most of the BRAF mutations have been identified using DNA-based techniques; however, Bösmüller et al. differentiated the BRAF V600E mutation using mutation-specific monoclonal antibody (VE1) specific for the BRAF V600E. This ability to immunostain the BRAF V600E mutant protein in serous ovarian tumour samples with low epithelial content demonstrates the practical usefulness of mutation-specific recognition by an antibody (VE1) (Bosmuller et al., 2013).

Prostate cancer, the most common cancer type in Western Europe and USA, has variable incidence of BRAF and/or KRAS mutations among different races (Ren et al., 2012; Shen et al., 2010). Three reports have recorded BRAF mutations in prostate carcinomas, and one of these showed no BRAF mutations in the American and German populations. However, 10.2% of prostate carcinomas have been identified as having BRAF mutations in the Korean population (Cho et al., 2006). In addition, 10% of prostate cancer cases have been characterised as having an activating BRAF mutation in the Asian population (Kollermann et al., 2010). This difference in BRAF mutation frequency has been characterised in many different ethnic backgrounds. According to recent evidence, a gain in the RAF gene copy number resulted in the activation of the RAS/RAF/MEK/ERK pathway was found to be the main contributing element in the regulation of prostate cancer in a Chinese population (Ren et al., 2012). However, in another report of Chinese patients, KRAS mutations at codons 12 and 13 were found in prostate cancer patients while no BRAF mutation was observed at codon 600 (Shen et al., 2010). Caucasian patients had results similar to the Chinese patients, suggesting that BRAF mutations are rarely found in prostate cancer and are not connected with tumour progression. Nevertheless, recurrent gene fusions have shown that the SLC45A3-BRAF and ESRP1-RAF1 fusions drive the molecular events occurring in advanced prostate and gastric cancers, as well as melanoma (Palanisamy et al., 2010). Subsequently, Kollermann et al. have argued that the emergence and the increased usage of BRAF-targeted therapies may have limited efficacy in treating prostate cancer patients (Kollermann et al., 2010).