Poster Presentation Advances in Neuroblastoma Research Congress 2016

Amplification of CDK4 and MDM2 is associated with atypical clinical features in high risk neuroblastoma patients (#159)

Susanne Fransson 1 , Hanna Kryh 2 , Niloufar Javanmardi 1 , Inge M Ambros 3 , Ana P Berbegall 4 , Ingrid Ora 5 , Rosa Noguera 4 , Jurate Asmundsson 6 , Bengt Sandstedt 6 , Peter F Ambros 3 , Ruth Ladenstein 3 , Per Kogner 7 , Tommy Martinsson 1
  1. Department of Medical and Clinical Genetics, Sahlgrenska Academy , University of Gothenburg, Gothenburg, Sweden
  2. Biotech Research and Innovation Center (BRIC) and Centre for Epigenetic, University of Copenhagen, Copenhagen, Denmark
  3. Children's Cancer Research Institute (CCRI), St. Anna Kinderkrebsforschung, Vienna, Austria
  4. Department of Pathology, Medical School, University of Valencia, Valencia, Spain
  5. Department of Pediatric oncology and Hematology, Clinical Sciences, Lund University, Lund, Sweden
  6. Unit for Pathology, Karolinska University Laboratories,, Stockholm, Sweden
  7. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden

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 SNP-microarrays we identified a 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. 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 extensive structural rearrangements on chromosome 12 leading to high grade amplification of CDK4 and MDM2. This tumor 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).