Copy number status and mutation analyses of anaplastic lymphoma kinase (ALK) gene in 90 sporadic neuroblastoma tumors

Bagci, Ozkan; Tumer, Sait; Olgun, Nur; Altungoz, Oguz

doi:10.1016/j.canlet.2011.11.013

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Volume 317, Issue 1 , Pages 72-77, 1 April 2012

Copy number status and mutation analyses of anaplastic lymphoma kinase (ALK) gene in 90 sporadic neuroblastoma tumors

Ozkan Bagci
- Department of Medical Biology and Genetics, Dokuz Eylul University, School of Medicine, Izmir, Turkey
- These authors contributed equally to this work.
Sait Tumer
- Department of Medical Biology and Genetics, Dokuz Eylul University, School of Medicine, Izmir, Turkey
- These authors contributed equally to this work.
Nur Olgun
- Department of Pediatric Oncology, Dokuz Eylul University, School of Medicine, Izmir, Turkey
Oguz Altungoz
- Department of Medical Biology and Genetics, Dokuz Eylul University, School of Medicine, Izmir, Turkey
- Corresponding author. Address: Department of Medical Biology and Genetics, Dokuz Eylul University, School of Medicine, 35340 Balcova, Izmir, Turkey. Tel.: +90 232 412 4605, mobile: +90 505 635 3435; fax: +90 232 412 4635.

Received 11 April 2011; received in revised form 5 November 2011; accepted 8 November 2011. published online 09 December 2011.

Abstract

Somatic and germline mutations of the anaplastic lymphoma kinase (ALK) gene were recently described in neuroblastoma (NB). In this study, we investigated the association of ALK copy number alterations with copy number status 2p24.1 amplicon harboring DEAD box polypeptide 1 (DDX1), MYCN and neuroblastoma-amplified (NAG) genes in 90 primary tumors of sporadic NB cases by multiplex ligation-dependent probe amplification (MLPA). We also performed mutation analysis of ALK gene by directly sequencing the exons 20–28 which cover the region that encodes juxtamembrane and kinase domains. A total of 39 (43.3%) NB cases revealed copy numbers alterations of ALK gene. There was highly significant association of ALK copy number gains with gains of one or more of the genes at 2p24.1 (DDX1, MYCN or NAG) in MYCN unamplified tumors (P<0.000). In addition, 15 of 17 MYCN amplified cases (88.2%) had aberrant ALK status. Solitary gain of ALK with normal copy number status of all other genes was observed only in one case. DNA sequencing of exons 20–28 of ALK revealed two different nucleotide changes in three cases leading to amino acid substitutions of F1245V and R1275Q in tyrosine kinase domain. In conclusion, the frequency of ALK mutations in NB is low and solitary copy number change of it is rarely observed.