Genetic Instability and Intratumoral Heterogeneity in Neuroblastoma with MYCN Amplification Plus 11q Deletion

Eva Villamón,Rosa Noguera,Samuel Navarro,Tommy Martinsson,Victoria Castel,Irene Tadeo,Ana P Berbegall,Marta Piqueras,Anna Djos

doi:10.1371/journal.pone.0053740

Abstract

Background/AimGenetic analysis in neuroblastoma has identified the profound influence of MYCN amplification and 11q deletion in patients’ prognosis. These two features of high-risk neuroblastoma usually occur as mutually exclusive genetic markers, although in rare cases both are present in the same tumor. The purpose of this study was to characterize the genetic profile of these uncommon neuroblastomas harboring both these high-risk features.MethodsWe selected 18 neuroblastomas with MNA plus 11q loss detected by FISH. Chromosomal aberrations were analyzed using Multiplex Ligation-dependent Probe Amplification and Single Nucleotide Polymorphism array techniques.Results and ConclusionThis group of tumors has approximately the same high frequency of aberrations as found earlier for 11q deleted tumors. In some cases, DNA instability generates genetic heterogeneity, and must be taken into account in routine genetic diagnosis.

Highlights

Genetic instability and the presence of genetically heterogeneous cell populations are well-known features in neuroblastoma (NB), the most common extra-cranial solid neoplasm in childhood [1,2,3,4,5]
In terms of Overall survival (OS) (Supplementary Figure S2), in the 3-year OS rate no statistically significant differences were found between patients with either hom and hetMNA plus 11q-deleted tumors and patients with homogeneous MNA (homMNA) w/ o 11q-del tumors (49.2% 613 versus 53% 69.5, p = 0.335), the slope was somewhat delayed in the latter group
Of the surviving patients described in this study, 60% correspond to cases with hetMNA; no significant prognostic differences in survival were found between patients with homMNA plus 11q-deleted tumors and the patients with hetMNA plus 11q deletion tumors

Summary

Introduction

Genetic instability and the presence of genetically heterogeneous cell populations are well-known features in neuroblastoma (NB), the most common extra-cranial solid neoplasm in childhood [1,2,3,4,5] This disease is characterized by a diverse behavior, and both prognosis and response to therapy can vary widely [6]. Genetic markers of NB include MYCN amplification (MNA) and allelic loss of 11q. The use of Multiplex Ligation–dependent Probe Amplification (MLPA), Comparative Genomic Hybridization (CGH) and Single Nucleotide Polymorphisms arrays (aSNP) has provided accurate and rapid identification of genome abnormalities at high resolution [8,9,10]. Numerical chromosome aberrations (NCAs), have been associated with excellent survival, while tumors with any type of segmental chromosome aberrations (SCAs) are related to a high-risk of relapse [1,11]

Objectives

Methods

Results

Conclusion