Abstract
BackgroundThe disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behavior and can thereby complement the prognostically favorable 1p/19q co-deletion.ResultsGenome-wide, 50 base pair single-end sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analyzed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors.ConclusionsCNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0471-6) contains supplementary material, which is available to authorized users.
Highlights
The disease course of patients with diffuse low-grade glioma is notoriously unpredictable
Clinical and histological data We studied 173 formalin-fixed paraffin-embedded (FFPE) samples from 98 diffuse low-grade glioma (LGG) patients, including spatially distinct regions and paired recurrent tumors, by shallow whole genome sequencing (WGS)
Copy number detection by shallow WGS in LGGs To obtain genome-wide copy numbers from the FFPE samples of our discovery cohort, we evaluated the use of shallow WGS
Summary
The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behavior and can thereby complement the prognostically favorable 1p/19q co-deletion. Diffuse low-grade gliomas (LGGs) are regarded as slow growing malignant brain tumors and patients can live up to 30 years with this disease. In a subset of patients the tumor exerts a more aggressive behavior and survival can be as short as two years [1]. Personalized timing of postoperative treatment is crucial to forestall progression in the latter group whilst preventing long-term side-effects for patients with more favorable prospects [2].
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