Caron, Alissa A

AbstractBackgroundGlioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)–wildtype GBM long-term survivors (LTS) to date.MethodsRetrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression.ResultsOf the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks.ConclusionsWhile our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.

AbstractPleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy‐number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A‐PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%–60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A‐PXA (93%), BRAF V600E (87%), and wild‐type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses −22 (n = 11), −14 (n = 7), −13 (n = 5). Losses and copy‐neutral loss of heterozygosity were significantly more common in A‐PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy‐number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A‐PXA with areas of distinct low‐ and high‐grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy‐number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy‐number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

AbstractPrognostic significance of histological anaplasia and BRAF V600E mutation were retrospectively evaluated in 74 patients with pleomorphic xanthoastrocytoma (PXA). Median age at diagnosis was 21.5 years (31 pediatric, 43 adult) and median follow‐up 7.6 years. Anaplasia (PXA‐AF), defined as mitotic index ≥ 5/10HPF and/or presence of necrosis, was present in 33 cases. BRAF V600E mutation was detected in 39 (of 60) cases by immunohistochemical and/or molecular analysis, all negative for IDH1 (R132H). Mitotic index ≥ 5/10HPF and necrosis were associated with decreased overall survival (OS; P = 0.0005 and P = 0.0002, respectively). In all cases except two, necrosis was associated with mitotic index ≥ 5/10HPF. Patients with BRAF V600E mutant tumors had significantly longer OS compared with those without BRAF V600E mutation (P = 0.02). PXA‐AF patients, regardless of age, had significantly shorter OS compared with those without (P = 0.0003). Recurrence‐free survival was significantly shorter for adult PXA‐AF patients (P = 0.047) only. Patients who either recurred or died ≤3 years from diagnosis were more likely to have had either PXA‐AF at first diagnosis (P = 0.008) or undergone a non‐gross total resection procedure (P = 0.004) as compared with patients who did not. This study provides further evidence that PXA‐AF behaves more aggressively than PXA and may qualify for WHO grade III “anaplastic” designation.