Abstract 2246: Identification of mutational signatures in high-risk neuroblastoma patients
Authors: Reinsbach Susanne E. , Larsson Malin , Martinez-Monleon Angela , Sjöberg Rose-Marie , Javanmardi Niloufar , Djos Anna , Kogner Per , Fransson Susanne , Lekholm Erik Larsson , Martinsson Tommy 
Published: August 2018

Abstract
Background: Mutational processes generate unique patterns of base substitutions generally referred to as mutational signatures. Mutational signatures can give insights into fundamental mutational processes underlying somatic mutations in tumors and have been shown to provide a starting point from which to evaluate therapeutic options. Neuroblastoma is clinically heterogeneous ranging from tendency of spontaneous regression to frequent formation of metastases. Earlier studies have identified several recurrent genetic alterations, including mutations in genes such as ALK and ATRX, as well as chromosomal rearrangements such as MYCN amplification, 11q deletion and 17 gain. Despite recent progress in the treatment of high-risk neuroblastoma, patients in this subgroup still have a poor prognosis, underscoring the need to further stratify patients in order to help inform clinical decision making.
Methods: Here, we sought to characterize high-risk patients and their underlying pattern of aberrations by conducting whole genome sequencing of 30 neuroblastoma patients. For each tumor/normal pair, the mutational landscape comprising single nucleotide and structural variants including copy number alterations was investigated. Non-negative matrix factorization was used to decompose single nucleotide variants to discover mutational signatures.
Results: De novo mutational signature analysis identified two mutational profiles (signature A and signature B) that were compared to known signatures of the pan-cancer study by Alexandrov et al. (2013). The landscape of signature A is closest to their signature 18 (0.97 cosine similarity) and revealed a strong bias towards C&gt;A substitutions mainly found in neuroblastoma, and signature B is closest to signature 5 (0.82 cosine similarity) identified in most of the cancers. Out of 13 patients with a clear dominance of signature A, 12 patients were classified with MYCN amplification or 11q deletion. Furthermore, 5 out of 6 patients with a main contribution of signature B were metastasis or relapse cases.
Conclusions: Our results suggest that what is currently considered to be the typical neuroblastoma signature is mainly present in primary high-risk patients whereas the mutational landscape is altered in more advanced stages of the disease. To better understand the connection between the identified signatures and the high-risk subgroup, we are currently investigating the genome wide landscape of the observed C&gt;A substitutions.
Citation Format: Susanne E. Reinsbach, Malin Larsson, Angela Martinez-Monleon, Rose-Marie Sjöberg, Niloufar Javanmardi, Anna Djos, Per Kogner, Susanne Fransson, Erik Larsson Lekholm, Tommy Martinsson. Identification of mutational signatures in high-risk neuroblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2246.