Neuroblastoma is one of the most genomically heterogeneous childhood malignances 
studied to date, and the molecular events that occur during the course of the 
disease are not fully understood. Genomic studies in neuroblastoma have showed 
only a few recurrent mutations and a low somatic mutation burden. However, none 
of these studies has examined the mutations arising during the course of 
disease, nor have they systemically examined the expression of mutant genes. 
Here we performed genomic analyses on tumors taken during a 3.5 years disease 
course from a neuroblastoma patient (bone marrow biopsy at diagnosis, adrenal 
primary tumor taken at surgical resection, and a liver metastasis at autopsy). 
Whole genome sequencing of the index liver metastasis identified 44 
non-synonymous somatic mutations in 42 genes (0.85 mutation/MB) and a large 
hemizygous deletion in the ATRX gene which has been recently reported in 
neuroblastoma. Of these 45 somatic alterations, 15 were also detected in the 
primary tumor and bone marrow biopsy, while the other 30 were unique to the 
index tumor, indicating accumulation of de novo mutations during therapy. 
Furthermore, transcriptome sequencing on the 3 tumors demonstrated only 3 out of 
the 15 commonly mutated genes (LPAR1, GATA2, and NUFIP1) had high level of 
expression of the mutant alleles, suggesting potential oncogenic driver roles of 
these mutated genes. Among them, the druggable G-protein coupled receptor LPAR1 
was highly expressed in all tumors. Cells expressing the LPAR1 R163W mutant 
demonstrated a significantly increased motility through elevated Rho signaling, 
but had no effect on growth. Therefore, this study highlights the need for 
multiple biopsies and sequencing during progression of a cancer and 
combinatorial DNA and RNA sequencing approach for systematic identification of 
expressed driver mutations.