High frequency of BRAF mutations in mucinous ovarian carcinoma of Taiwanese patients

Background In view of the encouraging clinical evidence of BRAF inhibitors that can treat some melanoma patients successfully, we aimed to investigate the status of BRAF mutations of primary mucinous ovarian carcinomas (MOC) in Taiwanese women, and apply the emerging paradigm classification of BRAF mutation groups. Methods DNA was extracted from micro-dissected tissue samples using the QIAamp® DNA FFPE Kit. The mutations of activation segment (exon 15), CR3 (conserved regions 3), kinase domain of the BRAF gene were analyzed using the highly sensitive BRAF mutant enriched kit (FemtoPath®) with subsequent Sanger sequencing method. Additionally, we extended our prior data of HER2 aberrations and KRAS mutation into this study in order to compare with the status of BRAF mutation. Results Out of the 20 cases tested, 16 (80%) harbored BRAF missense mutations. Their mutation profile and case number (n) were categorized as (1) class I: V600E (n = 1), V600M (n = 1); (2) class II: A598V (n = 1), T599I (n = 10); (3) class III: none (n = 0); and (4) unclassified variants: S602F (n = 2), dual T599I plus S602F (n = 1). The BRAF missense mutation (S602F) is novel. In addition, the prevalence of BRAF gene mutation is significantly higher than HER2 gene mutation (80% vs. 35%; p = 0.022,) and HER2 gene amplification (80% vs. 35%; p = 0.022), respectively. However, the mutation rates of BRAF and KRAS were not significantly different (80% vs. 60%; p = 0.289). Discussion Our results showed that BRAF mutation is not uncommon in primary MOC of Taiwanese. When taken together with previous published data, we found that the activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive, but simultaneously independent. However, they may even have a synergistic effect in tumorigenesis. Conclusions The BRAF variant with T599I stands the majority. These findings suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor in MOC. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage MOC patients carrying each class of BRAF mutation.