Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors

Abstract

Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty-three mutations that had not been reported previously, one of which was present in two of the four tumors. WES analysis also corroborated twenty-two mutations that were reported previously. No single mutation occurred in all four tumors or in all stage 4 tumors. Three of the four tumors harbored genes with CADD scores ≥20, indicative of mutations associated with human pathologies. The average depth of coverage ranged from 39.68 to 90.27, with >99% sequences mapping to the genome. In summary, WES identified sixty-five coding mutations including forty-three mutations not reported previously in primary neuroblastoma tumors. The three stage 4 tumors contained mutations in genes encoding protein products that regulate immune function or cell adhesion and tumor cell metastasis.

Focal Adhesion Kinase Inhibition Contributes to Tumor Cell Survival and Motility in Neuroblastoma Patient-Derived Xenografts

“…We have demonstrated that the inhibition of FAK in human neuroblastoma PDXs decreased the malignant phenotype of the PDX cells in vitro. We have previously demonstrated similar results when utilizing long-term passage neuroblastoma cell lines 8 ; however, the use of PDXs makes this study novel. PDXs that have been www.nature.com/scientificreports www.nature.com/scientificreports/ demonstrated to recapitulate the properties of the parent tumor provide a unique instrument for study of an actual tumor in vitro.…”

“…Neuroblastomas with both MYCN and FAK have been found to be over-expressed in patients with higher risk disease and poorer prognosis 6 . Additional mutations were identified with full exome sequencing but were chosen not to be investigated because of the clinical significance of MYCN amplification 8 . Thus, COA3 and COA6 were optimal PDXs to evaluate the effects of FAK inhibition; however, both of these tumors took two to six months to propagate in animals thereby making them practical only for in vitro experimentation.…”

Genomic profile of MYCN non-amplified neuroblastoma and potential for immunotherapeutic strategies in neuroblastoma

“…The mutation pro les of MYCN-ampli ed and non-ampli ed patients were compared, and mutations in mucin family genes were found to be more frequent in the MYCN-non-ampli ed subjects. Although mutations in the mucin gene family have been reported in NB [10], their biological relevance to NB remains unclear.…”

Genomic profile of MYCN non-amplified neuroblastoma and potential for immunotherapeutic strategies in neuroblastoma

“…The mutation pro les of MYCN-ampli ed and non-ampli ed patients were compared, and mutations in mucin family genes were found to be more frequent in the MYCN-non-ampli ed subjects. Although mutations in the mucin gene family have been reported in NB [30], their biological relevance to NB remains unclear.…”