Abstract
Allele-specific copy number analysis of tumors (ASCAT) assesses copy number variations (CNV) while accounting for aberrant cell fraction and tumor ploidy. We evaluated if ASCAT-assessed CNV are associated with survival outcomes in 56 patients with WHO grade IV gliomas. Tumor data analyzed by Affymetrix OncoScan FFPE Assay yielded the log ratio (R) and B-allele frequency (BAF). Input into ASCAT quantified CNV using the segmentation function to measure copy number inflection points throughout the genome. Quantified CNV was reported as log R and BAF segment counts. Results were confirmed on The Cancer Genome Atlas (TCGA) glioblastoma dataset. 25 (44.6%) patients had MGMT hyper-methylated tumors, 6 (10.7%) were IDH1 mutated. Median follow-up was 36.4 months. Higher log R segment counts were associate with longer progression-free survival (PFS) [hazard ratio (HR) 0.32, p < 0.001], and overall survival (OS) [HR 0.45, p = 0.01], and was an independent predictor of PFS and OS on multivariable analysis. Higher BAF segment counts were linked to longer PFS (HR 0.49, p = 0.022) and OS (HR 0.49, p = 0.052). In the TCGA confirmation cohort, longer 12-month OS was seen in patients with higher BAF segment counts (62.3% vs. 51.9%, p = 0.0129) and higher log R (63.6% vs. 55.2%, p = 0.0696). Genomic CNV may be a novel prognostic biomarker for WHO grade IV glioma patient outcomes.
Highlights
Glioblastoma is the most common intracranial malignancy with an age-adjusted incidence of 0.59 to 3.69 per 100,000 persons[1]
Tumors were at least partially methylated at methylguanine–DNA methyltransferase (MGMT) in 25 patients (44.6%) and harbored IDH1 mutations in 6 patients (10.7%)
To evaluate whether our Allele-specific copy number analysis of tumors (ASCAT) parameters were independent of known clinical risk factors, we evaluated a total of five variables (IDH1 mutations status, 1p19q co-deletion status, MGMT methylation status, Karnofsky performance status (KPS), and ASCAT parameter) in each multivariable progression-free survival (PFS) model due to limited sample size
Summary
Glioblastoma is the most common intracranial malignancy with an age-adjusted incidence of 0.59 to 3.69 per 100,000 persons[1]. Treatment can significantly impact their quality of life while conferring only marginal clinical benefit. Molecular genetics has become important in many malignancies, the study of which have yielded both prognostic and/or predictive biomarkers. The role and benefit of adjuvant radiotherapy and temozolomide have been aided by the predictive biomarkers in grade II-IV gliomas[4,5,6]. For grade III glioma patients with an IDH1-mutantion or 1p/19q co-deletion, chemoradiotherapy significantly improves survival compared to radiotherapy alone[6,7]. Genome-wide copy number analysis, an approach that assesses the number of gains and loses tiled across the genome, has been utilized with increasing frequency in a number of malignancies[8,9,10,11]. Median (range) Male Female ≤ 70 > 70 Biopsy GTR STR ≥ 60 Gy < 60 Gy Yes No Unknown Yes No Unknown
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