BRAF duplications and MAPK pathway activation are frequent in gliomas of the optic nerve proper

2012-09-01 13:36:35

J Neuropathol Exp Neurol; 2012 Sep; 71(9):789-94

Fausto J. Rodriguez, Azra H. Ligon, Iren Horkayne-Szakaly, Elisabeth J. Rushing, Keith L. Ligon, Natalie Vena, Denise I. Garcia, J. Douglas Cameron, and Charles G. Eberhart


Gliomas involving the optic nerve and other optic pathway structures (i.e. optic pathway gliomas) represent a specific subtype of astrocytoma with unique linicopathologic and biologic properties. Optic nerve gliomas may occur in the setting of neurofibromatosis type 1 (NF1) or sporadically and affect approximately 15% of children with NF1 (1). At the pathological level, NF1-associated and sporadic optic nerve gliomas are predominantly World Health Organization grade I pilocytic astrocytomas (PAs).

Whereas optic pathway gliomas are often considered as a group, some clinical data suggest that the site within the optic pathways at which they arise can affect their biology. Tumors in the hypothalamic region can behave aggressively, and these are often of the pilomyxoid variant. In contrast, it has long been recognized that tumors involving the optic nerve proper, particularly in the setting of NF1, are typically indolent and, in some instances, regress spontaneously. Because of the benign behavior and typical radiological appearance of optic nerve gliomas, in recent decades, they have rarely been biopsied, hampering investigations into their molecular basis.

Recent insights into the molecular mechanisms responsible for PAs have centered on the importance of mitogenactivated protein kinase (MAPK) pathway signaling. In NF1-associated tumors, the mechanism is biallelic NF1 gene inactivation. In sporadic PAs, the most frequent molecular alteration is a tandem duplication at chromosomal region 7q34 involving the BRAF kinase domain, which leads to a novel KIAA1549:BRAF fusion. Other alterations less commonly reported include BRAF
(V600E) point mutation, K-RAS mutations, SRGAP3:RAF1 fusions, small BRAF insertions (BRAFinsT), and the recently described FAM131B:BRAF fusion mediated by an interstitial deletion. The common biologic effect of all these alterations is MAPK pathway activation, which is an almost universal feature of PAs. Conversely, IDH1/2 mutations are absent in almost all instances, in contrast to diffuse gliomas where they are common.

Of interest, molecular alterations in PA, including optic pathway gliomas, appear to be site dependent. For example, global gene expression profiles in PA vary according to CNS site of origin. In addition, KIAA1549:BRAF fusions are most frequent in cerebellar PAs in many studies, with incidences ranging from 72% to 94%, whereas BRAF(V600E) is more typical of hemispheric PA. Although BRAF alterations are also frequent in optic pathway gliomas, with reported rates ranging from 43% to 69%, most of the tumors previously profiled were located in the hypothalamic region. The prevalence of BRAF alterations and MAPK pathway activation in gliomas of the optic nerve itself are therefore unclear. In this study, we took advantage of a unique historical archive containing a large number of optic nerve gliomas resected en bloc to perform targeted immunohistochemical and molecular analysis of tumors at a site from which tissue is rarely removed in
current clinical practice.

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