Bram Wilde

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Stephen Chrisomalis

Wayne State University

Dr. Surendra Pathak

Dr. Hari Singh Gaur University, Sagar(M.P.)

Samit Chakrabarty

University of Leeds

Giulio Pergola

Università degli Studi di Bari

Elyze Zomer

Eberhard Karls Universität Tübingen

Amado Salvador Peña

VUmc Amsterdam

Michel POULAIN

UCLouvain (University of Louvain)

Nafiu Amidu

University for Development Studies, Tamale, Ghana

Andrey Usachev

Russian State University for the Humanities

Ioannis Koutroubakis

University of Crete

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Emergence of new ALK mutations at relapse of neuroblastoma

In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigat... more In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution. We analyzed ALK mutations in 54 paired diagnosis-relapse neuroblastoma samples using Sanger sequencing. When an ALK mutation was observed in one paired sample, a minor mutated component in the other sample was searched for by more than 100,000× deep sequencing of the relevant hotspot, with a sensitivity of 0.17%. All nine ALK-mutated cases at diagnosis demonstrated the same mutation at relapse, in one case in only one of several relapse nodules. In five additional cases, the mutation seemed to be relapse specific, four of which were investigated by deep sequencing. In two cases, no mutation evidence was observed at diagnosis. In one case, the mutation was present at a subclonal level (0.798%) at diagnosis, whereas in another case, two different mutations resulting in identical amino acid changes were detected, one only at diagnosis and the other only at relapse. Further evidence of clonal evolution of ALK-mutated cells was provided by establishment of a fully ALK-mutated cell line from a primary sample with an ALK-mutated cell population at subclonal level (6.6%). In neuroblastoma, subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse. Given the potential of ALK-targeted therapy, the significant spatiotemporal variation of ALK mutations is of utmost importance, highlighting the potential of deep sequencing for detection of subclonal mutations with a sensitivity 100-fold that of Sanger sequencing and the importance of serial samplings for therapeutic decisions.

Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma

by Bram Wilde, Maté Ongenaert, G. Schleiermacher, Anneleen Decock, Robrecht Cannoodt, and Kimberly Verniers

Oncotarget, Jan 6, 2015

Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this stud... more Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were de...

Telomerase activation by genomic rearrangements in high-risk neuroblastoma

Nature, Jan 14, 2015

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of... more Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they...

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