Two BRAF p. V600 wild-type anaplastic PXA identified at the UCSF Brain Tumor Center were analyzed using targeted next-generation sequencing with the UCSF Clinical Cancer Genomics Laboratory. Patient clinical characteristics and tumor histopathology are summarized in Supplemental Table 1. Genomic profiling identified novel chromosomal rearrangements in both cases resulting in an in-frame fusion between the amino terminal portion of one gene encoding a homodimerization domain and the serine/threonine kinase domain of a RAF kinase family member. In PXA# 1 the predicted fusion protein contains exons 1-5 of NRF1, lacks the RAS-binding domain of BRAF (exons 4-8), and retains the serine/threonine kinase domain of BRAF (Fig. 1 a). Nuclear Respiratory Factor

Pleomorphic xanthoastrocytoma (PXA, WHO grade II) and anaplastic PXA (WHO grade III) are astrocytic neoplasms that commonly harbor an activating mutation in BRAF (p. V600E, c. 1799T> A)[4, 7], driving activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Currently, PXA is diagnosed based solely on histopathologic features. Yet recent reports based on DNA methylation suggest anaplastic PXA-like tumors can masquerade as glioblastoma (GBM)[3, 1]. Importantly these PXA-like tumors were associated with a more favorable prognosis than GBM and included both BRAF p. V600E mutant and non-mutant tumors in approximately equal proportions [3]. These findings suggest both histologic analysis and determination of BRAF p. V600E mutation status may not capture all tumors with the biologic behavior of