Abstract 4867: Exome- and whole genome sequencing for clinical evaluation and precision medicine in neuroblastoma
Authors: Monleon Angela Martinez , Reinsbach Susanne , Javanmardi Niloufar , Djos Anna , Sjoberg Rose-Marie , Kogner Per , Martinsson Tommy , Fransson Susanne 
Published: July 2017

Abstract
Background. Despite major progress in treatment of pediatric cancer, aggressive neuroblastoma (NB) still constitutes a major clinical problem. Currently, the event free survival of high-risk NB is about 40% implicating that 60% either don’t go into full remission or falls into relapse. Most relapses have an acquired drug resistance meaning that conventional treatment options may not work. Therefore, further studies of this group are of great importance. Massive parallel sequencing has now become a valuable tool in both cancer research and in clinical evaluation as it provides valuable information regarding patient specific alterations that might be used in targeted therapy.
Material and Methods. DNA from 54 patients in total have been subjects for massive parallel sequencing; 16 tumor/normal pairs and 27 single tumors have been analyzed using exome sequencing, 8 tumor/normal pairs with whole genome sequencing and three using both exome and whole genome sequencing. Exome sequences were mapped using BWA with GATK realignment followed by variant calling through SNPeff and copy number analysis trough ControlFreec. Whole genome data were analyzed using the CLC Genomic Workbench with annotation and filtering done in Ingenuity variant analysis software.
Results. On average, 14 somatic protein changing single nucleotide variants were detected per patient (range 2-71) with recurrent alterations mainly detected mainly in ALK. Predicted deleterious germ line alterations in well-established cancer genes were detected in three patients. Structural variants included genes such as ATRX and TERT, as described by others previously, but also novel homozygous focal deletions at chromosome 19. Shortest regions of overlapping deletions of this chr19 region include seven gens whereof CIC (Capicua) might be the most interesting in a cancer context. Copy number analysis of both exome- and whole genome sequencing gives genomic profiles that are comparable to the genome profiles generated from the SNP-microarrays that current are in clinical use. Specific breakpoints for structural variants could be detected in all sample subjects for whole genome sequencing as well as for all for all MYCN amplified neuroblastomas that subjects for exome sequencing.
Conclusions. Exome- and whole genome sequencing can be used for clinical evaluation of NB providing information regarding both constitutional and tumor specific alterations. The information can be used for clinical decision of patient specific therapeutic options such as ALK- or CDK4/6 inhibitors, but can also in rare cases give information regarding which treatments not to use. Furthermore, whole genome sequencing also gives the possibility to identify tumor specific structural alterations such as translocation breakpoints that can be used to monitor tumor burden in liquid biopsies.
Citation Format: Angela Martinez Monleon, Susanne Reinsbach, Niloufar Javanmardi, Anna Djos, Rose-Marie Sjoberg, Per Kogner, Tommy Martinsson, Susanne Fransson. Exome- and whole genome sequencing for clinical evaluation and precision medicine in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4867. doi:10.1158/1538-7445.AM2017-4867