Evolution of unbalanced gain of distal chromosome 2p in neuroblastoma

Abstract

Neuroblastoma, one of the most common tumors of childhood, presents at diagnosis with a vast number of recurrent chromosomal imbalances that include hyperdiploidy for whole chromosomes, partial loss of 1p, 3p, 4p, 11q, 14q, partial gain of 1q, 7q, 17q and amplification of MYCN. These abnormalities are nonrandomly distributed in neuroblastoma as loss of 3p and 11q rarely occur in MYCN amplified neuroblastomas. Here, we report on a patient who had a non-MYCN amplified 3p–/11q– neuroblastoma at diagnosis who subsequently developed a high level of MYCN amplification in bone marrow metastases 41 months after induction of complete remission. The tumor at diagnosis had low level unbalanced gain of distal 2p. In order to assess the frequency of low level gain of distal 2p in neuroblastoma, we examined the comparative genomic hybridization results from 60 neuroblastomas. Among non-MYCN amplified neuroblastomas, 8/45 (18%) had low level gain of distal 2p. Low level gain for a segment of 2p (i.e. a region larger than the 2p23→p24 undergoing amplification) was also detected in five of the 15 tumors that had high level MYCN amplification. The possibility that low level gain of distal 2p is a risk factor for high level MYCN amplification is discussed.

2p24 Gain Region Harboring MYCN Gene Compared with MYCN Amplified and Nonamplified Neuroblastoma

“…Reported rates for the few additional copies of the MYCN gene range from 6% to 13%; most of the studied tumors had one to three extra copies. [31][32][33] In accordance with these studies, 20 of the 25 patients in this group had one or two extra copies of the MYCN gene, and in another five patients, three extra copies were found.…”

“…A report of two cases of neuroblastoma without amplification at diagnosis but with low-level gain of the MYCN gene evolving into MYCN amplification at relapse have been described in the literature. [33][34] Valent et al 31 have shown simultaneous MYCN gain and amplification. The detailed study of these cases supplied information about several different mechanisms leading to increased MYCN copy number.…”

“…To the best of our knowledge, only three publications to date have addressed these findings and their possible influence on the disease outcome, but no definitive conclusions were reached. [31][32][33] In addition, several case reports have been published on the management of tumors with lowlevel gain in the MYCN region. 33,34 The aim of the present retrospective study was to investigate the cytogenetic and clinical characteristics of patients with neuroblastoma showing 2p/MYCN gain and to compare the findings with MYCN-amplified neuroblastoma and neuroblastoma with a balanced number of MYCN gene copies, and explore a possible impact on outcome.…”

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

“…Whereas breakpoints are widely dispersed along chromosome arms 1p, 2p, 3p and 17q, they lie closer together on chromosome 11q, at 11q23, in accordance with published data (Schleiermacher et al, 2004;Stallings et al, 2004;White et al, 2005;Spitz et al, 2006). Further studies using FISH or high-resolution CGH will be needed to map the breakpoints precisely.…”

Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand–receptor interactions

“…We also noticed that the Aug-α gene is located on the distal end of human chromosome 2p (Fig. 4E), a common hotspot for amplification in NBL, which is also the location of Alk and Mycn (7,32). These results may suggest that ALK inhibition may be clinically relevant beyond cases that have activating ALK mutations.…”