Distribution differences in prognostic copy number alteration profiles in IDH-wild-type glioblastoma cause survival discrepancies across cohorts

Toru Umehara,
Hideyuki AritaEmail author,
Ema Yoshioka,
Tomoko Shofuda,
Daisuke Kanematsu,
Manabu Kinoshita,
Yoshinori Kodama,
Masayuki Mano,
Naoki Kagawa,
Yasunori Fujimoto,
Yoshiko Okita,
Masahiro Nonaka,
Kosuke Nakajo,
Takehiro Uda,
Naohiro Tsuyuguchi,
Junya Fukai,
Koji Fujita,
Daisuke Sakamoto,
Kanji Mori,
Haruhiko Kishima and
Yonehiro Kanemura

Acta Neuropathologica Communications20197:15

https://doi.org/10.1186/s40478-019-0749-8

Received: 11 May 2019
Accepted: 30 May 2019
Published: 18 June 2019

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 PTENamong 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.