Abstract 495: Amplification of chromosomal regions 12q13-14 and 12q15 defines a distinct subgroup of high-risk neuroblastoma patients and is associated with atypical clinical features
Authors: Fransson Susanne M. , Kryh Hanna , Javanmardi Niloufar , Ambros Inge , Berbegall Ana , Ora Ingrid , Noguera Rosa , Asmundsson Jurate , Sandstedt Bengt , Ladenstein Ruth , Ambros Peter F. , Kogner Per , Martinsson Tommy 
Published: August 2015

Abstract
Neuroblastoma is a pediatric cancer of the sympathetic nervous system with wide heterogeneity regarding clinobiological subtypes, ranging from patients with tumors of spontaneous regression to patients with aggressive tumors with fatal outcome despite multimodal treatment. MYCN-amplification and 11q-deletion are important, although incomplete, markers of high-risk neuroblastoma. Thus, characterization of additional genomic alterations that can be used as prognostic and/or predictive markers is of clinical importance in order to provide best possible treatment.
From genomic profiles generated through high-density SNP microarrays we identified a group of neuroblastomas (14 primary tumors and two cell lines) with regional high grade amplification of one or multiple loci on the long arm of chromosome 12, commonly involving either chromosomal region 12q13-14, 12q15 or both. Amplification of these regions has also been reported in other malignancies such as liposarcoma, glioma and lung cancer. The two different 12q regions contains the potential oncogenic target genes; CKD4 (12q13-14) and MDM2 (12q15), involved in cell cycle progression and p53 regulation respectively. The CDK4 and MDM2 regions were co-amplified in 13/16 neuroblastoma samples while two tumors had CDK4 amplification in absence of MDM2 amplification and one tumor had MDM2 amplification without CDK4 amplification. Exome sequencing was performed for seven of the primary tumors with 12q-amplification. No novel protein altering single nucleotide variant (SNV) were detected within the amplicons with exception of a rare INHBE K222Q mutation in one patient. The exome sequencing also indicated that two tumors had a substantial number of additional rearrangements at subclonal level within the amplified regions, including a break of MDM2 in intron 8 for one of these patients. Interestingly, the majority of the 12q-amplified neuroblastoma was of abdominal origin, some with renal location with initial suspicion of Wilms’ tumor. Atypical metastatic pattern were also seen in this patient group showing low degree of bone marrow involvement favoring other metastatic sites such as lung, otherwise an uncommon localization in neuroblastoma.
The consistent co-amplification of two separate chromosome 12 regions in this subset of neuroblastoma suggests that these regions contain one or more genes with importance in tumor development. Our study indicates that CDK4 appears as main target in this 12q-amplified neuroblastoma subgroup although other genes such as MDM2 and FRS2 also could provide proliferative advantages. The 12q-amplified neuroblastoma exhibit distinct clinical features and can benefit from targeted therapy using a small molecule CDK4/CDK6 inhibitor such as LEE011 (Novartis).
Citation Format: Susanne M. Fransson, Hanna Kryh, Niloufar Javanmardi, Inge Ambros, Ana Berbegall, Ingrid Ora, Rosa Noguera, Jurate Asmundsson, Bengt Sandstedt, Ruth Ladenstein, Peter F. Ambros, Per Kogner, Tommy Martinsson. Amplification of chromosomal regions 12q13-14 and 12q15 defines a distinct subgroup of high-risk neuroblastoma patients and is associated with atypical clinical features. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 495. doi:10.1158/1538-7445.AM2015-495