Ethnic delineation of primary glioblastoma genome

Abstract

Glioblastoma (GBM) is the most malignant primary brain tumor in adults with substantial genomic alterations. The median survival is approximately 14.6 months, despite aggressive therapeutic intervention, which comprised of surgical resection, radiotherapy, and chemotherapy. Recent studies on cancer genomic have revealed crucial insights into dynamic molecular subgroups within GBM, which govern distinct clinical response and sensitivity of each individual to therapy. In the present study, we analyzed genomic composition of primary GBMs between two ethnic groups [IRCR (Institute of Refractory Cancer Research), and TCGA (The Cancer Genome Atlats)] to explore genomic and molecular features that constitute malignant behavior of glioblastoma based on distinct ethnicity. We identified enrichments of MAPK and p53 pathways in IRCR patients, while aberrant activation of Receptor Tyrosine Kinases (RTKs) were predominant in TCGA cohort. We also discovered differential clinical prognosis between two groups and explored essential features that present such diversity.

Keywords: ethnic; genetics; genomics; glioblastoma.

FIGURE 1

Overall survival of primary glioblastoma patients in TCGA and IRCR cohorts. To compare the survival outcome of primary glioblastoma patients between two cohorts, Kaplan‐meier survival curves were plotted. Survival outcome was significantly worse in TCGA cohorts (P = .00002 (Log‐rank test), median overall survival, 11.8 months vs 19.1 months). Younger patients (age < 50 years) were more prevalent in IRCR cohorts while older patients (age > 70 years) comprised up to one‐fourth of total population in TCGA cohorts (Figure 1B). Treatment strategy was significantly different between two cohorts; IRCR patients significantly had more temozolomide and chemotherapy other than temozolomide compared to TCGA cohorts (Figure 1C). Most of IRCR patients undertook the Stupp regimen and half of them completed the standard protocol while only 40% of total population had the Stupp regimen in TCGA cohorts (Table 1)

FIGURE 2

Genomic landscape of primary glioblastoma in TCGA and IRCR cohorts. (A) Each samples in TCGA and IRCR cohorts are annotated for their mutation, copy number alteration, exon skip and fusion. (B) EGFRvIII, EGFR,and FGFR fusions that were detected from two cohorts (136/126 in TCGA/IRCR) with RNA sequencing data are shown. (C) Focally amplification (log2(CN/2) > 1.58, red) and deletion (log2(CN/2) < −0.75, blue) are plotted on each chromosome. Bottom side: TCGA, Top side: IRCR

FIGURE 3

Molecular subtypes of primary glioblastoma in TCGA and IRCR cohorts. MES, Mesenchymal; CL, Classical; PN, Proneural; NL, Neural

FIGURE 4

Landscape of major pathway alterations in primary GBM. Overall analysis proportion is summarized for PI3K/MAPK, p53 and Rb regulatory pathway. Amplification (log2(CN/2) > 1.58) and deletion (log2(CN/2) < −0.75, blue)