Oral Presentation Advances in Neuroblastoma Research Congress 2016

TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors (#37)

Jan Koster 1 , Linda J Valentijn 1 , Danny A Zwijnenburg 1 , Nancy E Hasselt 1 , Peter van Sluis 1 , Max van Noesel 2 , Rani E George 3 4 , Godelieve AM Tytgat 2 5 , Jan J Molenaar 1 , Rogier Versteeg 1
  1. Oncogenomics, Academic Medical Center (AMC), Amsterdam, nh, Netherlands
  2. Princes Maxima Centrum, Utrecht
  3. Dana-Farber Cancer Institute, Boston
  4. Boston Children's Hospital, Boston
  5. 4Pediatric Oncology, Academic Medical Center (AMC), Amsterdam

Recently, we have presented the genomic landscape of 87 neuroblastoma tumors. As recurrent somatic mutations are rare in this cancer and enhancer hijacking has been demonstrated in medulloblastoma, we hypothesized that recurrent structural variations could be identified in our neuroblastoma cohort extended to 108 cases.

Methods

Whole genome sequencing was performed on a total of 108 tumor/lymphocyte DNA samples. Somatic structural variations were identified and analyzed for recurrent locations. Coverage based breakpoint, mRNA expression, telomere length, and super-enhancer analyses were performed.

Results

For each Mb region in the genome, we calculated the number of tumors with structural events. The second-most frequently affected region after MYCN was located around the TERT locus in 23% of the high stage tumors. TERT was the only gene in the vicinity with a significantly increased expression in the rearranged cases as compared to normal cases (p=8.51x10-5, Wilcoxon Ranksum). Most of the rearrangements occurred TERT. We identified neuroblastoma-specific super-enhancers in seven of the translocation partners, a significant enrichment over random breaks (p<0.003). TRF analysis showed increased telomere lengths for rearranged cases, confirming increased telomere repeat counts in the corresponding sequence data. TERT rearrangements were associated with poor prognosis (p=0.04 Logrank) and almost mutually exclusive with MYCN amplification and ATRX defects. In multivariate analyses all 3 showed independent prognostic significance.

Conclusions

TERT rearrangements form the second-most frequent gene defect in neuroblastoma, after MYCN. TERT defects are almost mutually exclusive with ATRX and MYCN defects, and each identifies a separate group at very high risk. These tumors have elevated TERT expression due to rearrangement of the upstream 30 kb or downstream 40 kb regions and in over half of the informative breakpoints, TERT was ostensibly activated by hijacking a super-enhancer. Pharmacological inhibition of TERT might in future improve the outcome for this patient group.