Abstract
The diagnosis and prognostication of glioblastoma (GBM) remain to be solely dependent on histopathological findings and few molecular markers, despite the clinical heterogeneity in this entity. To address this issue, we investigated the prognostic impact of copy number alterations (CNAs) using two population-based IDH-wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). The molecular disproportions between these cohorts were dissected in light of cohort differences in GBM. The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The somatic landscape around CNAs was analyzed for 212 KNBTG cases and 359 TCGA cases. Next, the clinical impacts of CNA profiles were investigated for 140 KNBTG cases and 152 TCGA cases treated by standard adjuvant therapy using temozolomide-based chemoradiation. The comparative profiling indicated unequal distribution of specific CNAs such as EGFR, CDKN2A, and PTEN among the two cohorts. Especially, the triple overlap CNAs in these loci (triple CNA) were much higher in frequency in TCGA (70.5%) than KNBTG (24.3%), and its prognostic impact was independently validated in both cohorts. The KNBTG cohort significantly showed better prognosis than the TCGA cohort (median overall survival 19.3 vs 15.6 months). This survival difference between the two cohorts completely resolved after subclassifying all cases according to the triple CNA status. The prognostic significance of triple CNA was identified in IDH-wild-type GBM. Distribution difference in prognostic CNA profiles potentially could cause survival differences across cohorts in clinical studies.
Highlights
The recent comprehensive molecular analysis of glioblastoma (GBM), including The Cancer Genome Atlas (TCGA) projects, has revealed the tumor genetic landscape and various functional relations between genes and pathways in tumorigenesis [4]
Long before discovering IDH1/2 mutation, a chromosomal aberration in GBM was initially detected by gain of EGFR [18], which was subsequently followed by various copy number alteration (CNA)
Association or tendency toward co-occurrence was observed among TERT promoter mutation, EGFR gain/ amp, and PTEN deletion with each other
Summary
The recent comprehensive molecular analysis of glioblastoma (GBM), including The Cancer Genome Atlas (TCGA) projects, has revealed the tumor genetic landscape and various functional relations between genes and pathways in tumorigenesis [4]. The most important molecular change in glioma is IDH1/2 mutations [24, 29], which define biological characteristics in glioma through the change of global DNA methylation and histone modification. Some CNAs, such as loss of chromosome 10 [23] and NFKBIA deletion [2], were reported to be solely associated with survival in GBM patients Since their correlation with survival has not been fully validated in the subsequent studies, no consensus has been reached as to which CNA has a universal prognostic value beyond the WHO grading of GBM
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