Abstract
BACKGROUND: Mutations in the neurofibromin 1 (NF1) tumor suppressor gene are common in GBM. We sought to characterize the mutational and clinical landscape of these NF1-mutated GBMs. METHODS: IRB approval was granted to collect clinical information on GBMs with NF1 and EGFR alterations (control group) identified by hybridization capture-based next-generation sequencing. Progression free survival (PFS) was based on the Macdonald criteria. RESULTS: 35 GBMs harboring a NF1-mutation were identified in 17 men and 18 women. Median age was 57 (range 33-76); 9% underwent biopsy and 91% resection. All patients received radiotherapy, 97% received concurrent temozolomide, and 88% received adjuvant temozolomide. Genomic alterations in NF1 were evenly distributed throughout the gene without hot spot mutations. Associated genetic alterations occurred in PTEN (60%), TERT promoter (60%), CDKN2A/B locus (51%), TP53 (31%), PIK3CA (20%), RB1 (14%), and STAG2 (11%). Contrast enhancement during the first three months post-radiotherapy was identified in 74% of NF1-mutated GBMs and 57% of EGFR-altered GBMs, resulting in a difference in PFS: 3.3 vs. 4.8 months (p = 0.018)–without a difference in overall survival (OS), p = 0.61. Furthermore, a shorter PFS was identified in NF1-mutated GBMs with a loss of CDKN2A/B (3.2 vs 5.1 mo, p = 0.006) with a trend towards shorter survival (p = 0.14). There was no difference in PFS in EGFR-altered GBMs with a loss of CDKN2A/B (p = 0.71). 7/7 tumors with NF1 mutations and early contrast enhancement were hypermetabolic on PET and 17/18 tumors with early contrast enhancement were hyperperfused on MR perfusion–there was no difference in OS when patients with early contrast enhancement were continued on temozolomide rather than changed to salvage therapy (p = 0.76). CONCLUSION: NF1-mutated GBMs are associated with PTEN, CDKN2A/B, and TP53 mutations and have a higher rate of early contrast enhancement post-radiotherapy, particularly the tumors with associated loss of the CDKN2A/B locus.
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