Gliosarcoma: distinct molecular pathways and genomic alterations identified by DNA copy number/SNP microarray analysis.

PURPOSE: Gliosarcoma is a histologic variant of glioblastoma (GBM), and like GBM carries a poor prognosis. Median survival is less than one (1) year with less than 5% of patients alive after 5 years. Although there is no cure, standard treatment includes surgery, radiation and chemotherapy. While very similar to GBM, gliosarcoma exhibits several distinct differences, morphologically and molecularly. Therefore, we report a comprehensive analysis of DNA copy number changes in gliosarcoma using a cytogenomic DNA copy number (CN) microarray (OncoScan®). METHODS: Cytogenomic DNA copy number microarray (OncoScan®) was performed on 18 cases of gliosarcoma. MetaCore™ enrichment was applied to the array results to detect associated molecular pathways. RESULTS: The most frequent alteration was copy number loss, comprising 57% of total copy number changes. The number of losses far exceeded the number of amplifications (***, < 0.001) and loss of heterozygosity events (***, < 0.001). Amplifications were infrequent (4.6%), particularly for EGFR. Chromosomes 9 and 10 had the highest number of losses; a large portion of which correlated to CDKN2A/B loss. Copy number gains were the second most common alteration (26.2%), with the majority occurring on chromosome 7. MetaCore™ enrichment detected notable pathways for copy number gains including: HOXA, Rho family of GTPases, and EGFR; copy number loss including: WNT, NF-kß, and CDKN2A; and copy number loss of heterozygosity including: WNT and p53. CONCLUSIONS: The pathways and copy number alterations detected in this study may represent key drivers in gliosarcoma oncogenesis and may provide a starting point toward targeted oncologic analysis with therapeutic potential.

Clinical Validation and Diagnostic Utility of Optical Genome Mapping for Enhanced Cytogenomic Analysis of Hematological Neoplasms.

The current standard-of-care cytogenetic techniques for the analysis of hematological malignancies include karyotyping, fluorescence in situ hybridization, and chromosomal microarray, which are labor intensive and time and cost prohibitive, and they often do not reveal the genetic complexity of the tumor, demonstrating the need for alternative technology for better characterization of these tumors. Herein, we report the results from our clinical validation study and demonstrate the utility of optical genome mapping (OGM), evaluated using 92 sample runs (including replicates) that included 69 well-characterized unique samples (59 hematological neoplasms and 10 controls). The technical performance (quality control metrics) resulted in 100% first-pass rate, with analytical performance (concordance) showing a sensitivity of 98.7%, a specificity of 100%, and an accuracy of 99.2%. OGM demonstrated robust technical, analytical performance, and interrun, intrarun, and interinstrument reproducibility. The limit of detection was determined to be at 5% allele fraction for aneuploidy, translocation, interstitial deletion, and duplication. OGM identified several additional structural variations, revealing the genomic architecture in these neoplasms that provides an opportunity for better tumor classification, prognostication, risk stratification, and therapy selection. Overall, OGM has outperformed the standard-of-care tests in this study and demonstrated its potential as a first-tier cytogenomic test for hematologic malignancies.

Copy number assessment in the genomic analysis of CNS neoplasia: An evidence-based review from the cancer genomics consortium (CGC) working group on primary CNS tumors.

The period from the 1990s to the 2010s has witnessed a burgeoning sea change in the practice of surgical neuropathology due to the incorporation of genomic data into the assessment of a range of central nervous system (CNS) neoplasms. This change has since matured into the adoption of genomic information into the definition of several World Health Organization (WHO)-established diagnostic entities. The data needed to accomplish the modern diagnosis of CNS neoplasia includes DNA copy number aberrations that may be assessed through a variety of mechanisms. Through a review of the relevant literature and professional practice guidelines, here we provide a condensed and scored overview of the most critical DNA copy number aberrations to assess for a selection of primary CNS neoplasms.

Genomic copy number variation correlates with survival outcomes in WHO grade IV glioma.

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.

Alcohol use by undergraduate students on their 21st birthday: predictors of actual consumption, anticipated consumption, and normative beliefs.

Recent research has identified celebration of a 21st birthday as an environmental event during which many college students engage in risky levels of alcohol consumption. The current study examined the relationship between personality and different aspects of alcohol use during 21st birthday celebrations: actual amount consumed for those who had turned 21, anticipated amount consumed for those under the age of 21, and normative beliefs regarding the amount other students consume on their 21st birthdays. Sensation seeking and impulsivity both displayed significant bivariate relationships with all three aspects of 21st birthday drinking. Personality traits did not contribute unique variance to actual 21st birthday drinking after the effects of typical alcohol consumption were accounted for in the models. Impulsivity contributed unique variance to models accounting for anticipated drinking and normative beliefs. Additional research is necessary to better understand the role personality variables play on alcohol consumption during 21st birthday celebrations.