Poster Presentation Advances in Neuroblastoma Research Congress 2016

Alternative lengthening of telomeres in primary neuroblastoma specimens – a genomic, epigenomic & proteomic approach (#355)

Sabine Hartlieb 1 , Lars Feuerbach 2 , Lina Sieverling 2 , Michal Nadler-Holly 3 , Katharina Deeg 4 , Matthias Selbach 3 , Benedikt Brors 2 , Karsten Rippe 4 , Frank Westermann 1
  1. Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  2. Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  3. Proteome Dynamics, Max Delbrück Center for Molecular Medicine, Berlin, Germany
  4. Genome Organisation & Function, German Cancer Research Center (DKFZ), Heidelberg, Germany

Background: In order to gain unlimited replicative potential, every cancer cell has to develop a mechanism to maintain its telomeres. Similar to the majority of all cancer cells, MYCN-amplified neuroblastoma (NB) tumors as well as TERT-translocated tumors accomplish telomere maintenance by telomerase activation. Interestingly, cancer cells can also elongate telomeres by telomerase-independent mechanisms referred to as alternative lengthening of telomeres (ALT), which is also found in a subgroup of high-risk NB patients.

Methods: ALT-positive patients are identified by screening a NB patient tumor cohort comprising about 800 tumors using the presence of C-Circles, which are a reliable marker to determine ALT activity. Subsequently, ALT tumors will undergo a comprehensive analysis using high coverage whole genome sequencing, whole proteome analysis and epigenetic analysis of DNA methylation and histone modifications.

Results: To date, 19 of 268 tested primary tumors were identified as ALT-positive. 90% of those were high-risk stage 4 tumors and all came from patients being older than 1.5 years. ALT activity was found to be mutually exclusive to amplified MYCN. Furthermore, 95% of the ALT tumors had the same genomic subtype harboring segmental and numerical aberrations without an amplified MYCN gene. Similar patterns of chromosomal aberrations, including a deletion in chromosome 11q and gains in chromosome 17q and chromosome 7, were observed in these patients.

Conclusion: The combined analysis of high coverage whole genome sequencing data, whole protein expression analysis and epigenetic profiling will enable a unique characterization of the ALT-positive neuroblastoma tumors. This study has the potential to deepen the knowledge about the general mechanisms of ALT activation and to reveal unknown vulnerabilities and potential therapy targets for this subgroup of high-risk NB patients as well as for ALT-positive tumors form other entities.