Distribution differences in prognostic copy number alteration profiles in IDH-wild-type glioblastoma cause survival discrepancies across cohorts
Distribution differences in prognostic copy number alteration profiles in IDH-wild-type glioblastoma cause survival discrepancies across cohorts
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DOI：
10.1186/s40478-019-0749-8
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发表时间：
2019-06-18
影响因子：
7.1
通讯作者：
Kanemura, Yonehiro
中科院分区：
文献类型：
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作者：
Umehara, Toru;Arita, Hideyuki;Kanemura, Yonehiro
尽管胶质母细胞瘤（GBM）的临床异质性很大，但其诊断和鉴别仍仅依赖于组织病理学表现和少数分子标志物。为了解决这个问题，我们使用两个基于人群的IDH野生型GBM队列研究了拷贝数改变（CNA）的预后影响：一个原始的日本队列和一个来自癌症基因组图谱（TCGA）的数据集。根据GBM的队列差异，分析了这些队列之间的分子不成比例。日本队列收集自Kansai Molecular Diagnosis Network for CNS tumors（KNBTG）中登记的病例。分析了212例KNBTG和359例TCGA患者CNA周围的躯体景观。接下来，研究了使用基于替莫唑胺的放化疗的标准辅助疗法治疗的140例KNBTG病例和152例TCGA病例的CNA谱的临床影响。比较分析表明，两个队列中特定CNA（例如EGFR、CDKN 2A和PTEN）的分布不均匀。特别是，这些基因座中的三重重叠CNA（三重CNA）在TCGA中的频率（70.5%）远高于KNBTG（24.3%），并且其预后影响在两个队列中得到了独立验证。KNBTG队列的预后明显好于TCGA队列（中位总生存期19.3 vs 15.6个月）。根据三重CNA状态对所有病例进行亚分类后，两个队列之间的生存差异完全消除。在IDH-野生型GBM中鉴定了三重CNA的预后意义。预后CNA谱的分布差异可能导致临床研究中队列间的生存差异。
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 15.6months). 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.