Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas

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.

Landscape of chromosomal copy number aberrations in gangliogliomas and dysembryoplastic neuroepithelial tumours

“…For comparison of GNT with diffuse growth patterns with AII, readily available CNA data of 38 AIIs from an low‐grade glioma (LGG) cohort of adults were included. These patients and data have been described before [22].…”

Molecular profiling of gliomas: potential therapeutic implications

“…In newly diagnosed tumor, analysis of non-representative sample of the tumor (e.g., biopsy in the periphery of the lesion) may omit important pathological and/or molecular features for medical management of the patients. Similarly, temporal heterogeneity supports re-biopsy of recurrent tumor to confirm pathological recurrence/progression and to detect additional molecular alterations helping in prognostic evaluation and therapy decision-making (e.g., druggable abnormalities) [82][83][84].…”

Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas

“…TCGA level 3 copy number data were publicly available at the time of download and mapped to NCBI36/hg18. These level 3 data involve beginning and end positions of chromosomal segments with deflection values, resulting from TCGA preprocessing (for level definitions and preprocessing see [31]). Segment values were converted to CNA discreet categories by setting thresholds whereby a log2 ratio of >0.20 is gain, < -0.23 is loss and all other values are normal copy number; these values correspond to 30% of the tumor cells with that CNA.…”