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RESEARCH PRODUCT

Abstract 2435: Amplification of CDK4 and MDM2 is associated with atypical clinical features in high risk neuroblastoma patients

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Abstract 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 treatment possible. By using SNP-microarrays we identified a small group of neuroblastomas with high grade amplification of one or multiple loci on 12q, commonly involving the potential oncogenic target genes CKD4 (12q13-14) and/or MDM2 (12q15). The CDK4 and MDM2 regions were co-amplified in 13/16 samples, two tumors had CDK4-amplification in absence of MDM2-amplification while one tumor had MDM2-amplification without CDK4-amplification. Exome sequencing was performed on seven tumors and whole genome sequencing (WGS) was performed on tumor and constitutional DNA from one patient with 12q-amplification. No novel protein altering SNVs were detected within the amplified regions except a rare INHBE mutation in one patient. The tumor examined with WGS show high degree of structural rearrangements including chromothriptic features on chromosome 12 leading to high grade amplification of CDK4 and MDM2. This sample displayed 21 somatic protein changing alterations although not in any gene with known function in chromatin stability or DNA repair. Interestingly, the majority of the 12q-amplified neuroblastomas were 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. The consistent co-amplification of two separate chromosome 12 regions in this subset of neuroblastoma suggests that there are one or more genes with importance in tumor development/progression. 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 neuroblastomas exhibit distinct clinical features and may 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 M. Ambros, Ana P. Berbegall, Ingrid Ora, Rosa Noguera, Jurate Asmundsson, Bengt Sandstedt, Peter F. Ambros, Per Kogner, Tommy Martinsson. Amplification of CDK4 and MDM2 is associated with atypical clinical features in high risk neuroblastoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2435.