Srishti Rajeev

Glioblastoma multiforme (GBM) is a highly aggressive, complex, and treatment-resistant form of brain cancer associated with poor clinical outcomes. Chromosomal instability (CIN), which refers to the abnormal separation, number, or structure of chromosomes seen in tumors, is a cancer hallmark that has been associated with poor prognosis and treatment resistance in GBM. Here, we sought to evaluate the prevalence of CIN in GBM and its association with clinical and molecular features using a pan-cancer cohort from the City of Hope (n=1,228 patients across cancer types, 14 patients with GBM) and public GBM data from The Cancer Genome Atlas (TCGA), focusing on patients who received standard of care radiation and chemotherapy (n=212 patients with GBM). The CINmetrics R package was used to calculate five measures of CIN: total aberration index, break points, fraction of genome altered, base segments altered, and copy number aberrations. CIN was common in GBM tumors, with GBM ranking within the top five tumor types across the City of Hope cohort for a majority of these metrics. Total aberration index (TAI) measures both the magnitude and genomic size of copy number aberrations, and has not been studied before in GBM. In the TCGA GBM cohort, low TAI showed a general trend toward shorter progression-free survival and overall survival, but log-rank statistical analyses revealed this difference was not statistically significant. Out of the remaining four metrics, both higher copy number aberrations and higher break points were significantly associated with longer overall survival (p<0.05) but not progression-free survival, as compared to those with low copy number aberrations and break points, suggesting lower values of these CIN metrics are associated with poorer prognosis in patients who receive standard-of-care radiation and chemotherapy. This association was independent of MGMT methylation status, a known prognostic biomarker in GBM. Tumors with genomic alterations in mitotic spindle genes showed significantly higher copy number aberration and break point values than tumors without mutations in these genes (p<0.05, unpaired Welch’s t-test). Differential gene expression analysis performed with DESeq2 revealed 78 genes differentially expressed in samples with high copy number aberrations and 65 differentially expressed genes in samples with high break points as compared to tumors with low CIN values. A majority of these differentially expressed genes (n=44) were identified in both comparisons, suggesting that a common gene expression signature underlies GBM tumors with low chromosomal instability. Together, these results demonstrate that chromosomal instability is common in GBM and that CIN measures, specifically low copy number aberrations and low break points, may help define a subset of GBM patients with poorer clinical responses to standard-of-care therapy.