Читать книгу Intracranial Gliomas Part II - Adjuvant Therapy - Группа авторов - Страница 32

The presence of an activating mutation at codon V600E of the proto-oncogene BRAF(BRAF^V600E) was frequently observed in cases of papillary thyroid carcinoma, colorectal cancer, melanoma and non-small cell lung cancer. It has also been identified in 60–100% of PXA (including those with anaplastic features), 50–60% of gangliogliomas, and 20–33% of extracerebellar (lobar, diencephalic, thalamic, brainstem) PA [13, 14, 17]. Moreover, recently BRAF^V600E mutations have been revealed in 39% of pediatric secondary (but not in primary) HGG and in their low-grade predecessors [39], as well as in 54% of the rare epitheliod variant of GBM (mainly in children and young adults) [16].

BRAF encodes the protein B-Raf, which is a member of the RAF kinase family of growth signal transduction protein kinases. It plays an important role in regulating the MAPK/ERK (mitogen-activated protein kinases/extracellular-signal-regulated kinases) signaling pathway (also known as the Ras-Raf-MEK-ERK pathway) regulating cell division and differentiation. IHC provides 100% sensitivity and 98% specificity for detection of the BRAF^V600E mutation [14].

Although in PA BRAF^V600E mutation is strongly associated with extracerebellar tumor location, the most characteristic molecular event in cerebellar tumors, particularly in pediatric patients, is BRAF-KIAA1549 fusion. It is encountered in 60–85% of such cases and is caused by tandem duplication at 7q34, and leads to activation of the MAPK/ERK signaling pathway [13, 17, 70]. In fact, it is currently believed that pediatric PA is predominantly a single pathway disease, and that upstream contributors to the MAPK/ERK pathway activation play a major role in determining the tumor biology and clinical course [17].

In pediatric patients identification of BRAF-KIAA1549 fusion may be helpful for differentiation of PA from DA [70, 71]. The latter tumors in children usually harbor mutually exclusive mutations of MYB/MUBL1, FGFR1, or BRAF^V600E [14, 17]. Additionally, BRAF-KIAA1549 fusion is associated with a dramatically reduced risk of malignant transformation of pediatric LGG. Finally, identification of BRAF^V600E mutation gives a potential for specific antitumor kinase inhibitor therapy [16].