Analysis of the BRAF(V600E) Mutation in Central Nervous System Tumors

Abstract

BRAF(V600E) mutations are involved in the development of melanoma, colon cancer, and papillary thyroid carcinoma. These mutations are also found in primary brain tumors at low to moderate frequencies. In this study, we investigated a series of brain tumors to determine the prevalence and associated clinicopathologic features of BRAF(V600E) mutations. By direct sequencing, we analyzed 223 brain tumors, including 51 gangliogliomas (GGs), 45 pilocytic astrocytomas (PAs), 12 pleomorphic xanthoastrocytomas (PXAs), 35 glioblastomas (GBs), 28 anaplastic astrocytomas (AAs), 44 oligodendroglial tumors (ODGs), 3 anaplastic oligoastrocytomas, and 5 diffuse astrocytomas. Thirty-six cases (16.1%) exhibited the BRAF(V600E) mutation, including 66.7% of PXAs, 23.5% of GGs, 15.6% of PAs, and 9.7% of the malignant gliomas; the latter included 14.3% of AAs, 8.6% of GBs, and 4.5% of ODGs. Copy number aberration at the 7q34 (BRAF) locus was found in 73.1% of PAs and 50% of PXAs. 9p Homozygous deletion was found in 66.7% of PXAs, but it was not correlated with the BRAF(V600E) mutation. Patients' age, sex, histologic grade, and progression-free survival were also not correlated with the BRAF(V600E) mutation. The BRAF(V600E) mutation in brain tumors did not have prognostic value but is certainly a diagnostic marker and therapeutic target, not only for pediatric low-grade gliomas but also for malignant gliomas, even though the rate of mutation was not high. These results should be verified in a larger study with more cases and a longer follow-up period to overcome the limitation of small sample size.

Figure 1

(A) The result of direct sequencing of BRAF^V600E mutation (left upper). (B) The FISH result of 9p21.3 (p16). The left figure is normal control and the right figure is the tumor cells of PXA with HD of 9p21.3 (CDKN2A). The spectrum orange probe is LSI CDKN2A, and the spectrum green probe is CEP9. (C) BRAF^V600E and HD of 9p21.3 are found in 66.7% (8 of 12 cases) of PXAs. However, they are not statistically correlated (P = .661).

Figure 2

Kaplan-Meier analysis of the progression-free survival according to BRAF^V600E mutation status in patients with GG. The BRAF^V600E-mutated tumors have a tendency of better progression-free survival, but it is not statistically significant (P = .143).

Figure 3

The FISH result of 7q34 (BRAF). (A) Normal control. (B) Tumor cells of PA with chromosomal gain of BRAF. The spectrum gold probe is LSI BRAF, and the spectrum green probe is CEP7. (C) The tumor cells of PXA, which showed concomitant gains of spectrum gold probe (BRAF) and the spectrum green probe (chromosome centromeric probes on chromosome 7), which is compatible with polysomy.