High frequency of BRAF mutations and concomitant KRAS mutations in Taiwanese ovarian clear cell carcinoma
Given encouraging clinical evidence of BRAF inhibitors for melanoma, etc., we investigated BRAF mutation status in ovarian clear cell carcinoma (OCCC) from Taiwanese women and assessed the association of BRAF mutation with KRAS mutation. DNA was extracted from microdissected tissue samples and analyzed for BRAF mutations in exon 15, around the activation segment (AS), using a highly sensitive BRAF mutant enrichment kit (FemtoPath®) with Sanger sequencing. All 17 OCCC cases were evaluated. 16 (94.12 %) harbored BRAF missense mutations, categorized as Class I - p.V600M (n = 3); Class II - p.A598V (n = 8), p.T599I (n = 10); Class III - none; and unclassified (UC) variants - p.A598T (n = 1), p.A598I (n = 1), p.S602A (n = 1), p.S602F (n = 7). These mutations occurred as single-point (n = 6), double-point (n = 5), or triple-point (n = 5) mutations. The most frequent mutation observed was p.T599I (n = 10), followed by p.A598V (n = 8) and p.S602F (n = 7). The p.A598I, p.S602A, and p.S602F are novel BRAF alterations. Merging our previous KRAS data, we found that concurrent KRAS and BRAF mutations in 11 of 17 cases (64.71 %) suggest a possible synergistic effect in OCCC tumorigenesis. Activating BRAF mutations are common in OCCC in Ascian Taiwanese, with p.T599I most prevalent. This suggests the potential for reduced response to current BRAF V600 inhibitors but possible sensitivity to dual BRAF/MEK or MEK inhibitors, other multi-targeted approaches, and new avenues for cancer immunotherapy. Further studies are encouraged to investigate the clinical benefits of these approaches for advanced OCCC with various BRAF mutation classes.