Abstract 4833: A genomic portrait of tumor progression using next-generation sequencing

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Genetic alterations are thought to enable cancers to proliferate and survive more effectively or to resist cytotoxic therapies. However, the molecular basis of tumorigenesis and progression is not fully understood. In order to understand the genetic aberrations underlying tumor progression in refractory neuroblastoma, we performed next-generation sequencing on the whole exomes of three sequential tumor samples taken from a high-risk stage 4 neuroblastoma patient at diagnosis, after cytotoxic therapies, and at death, paired with a germline DNA sample from the same patient. Each genomic DNA sample was first partitioned using SureSelect whole human exome kits targeting ∼38Mb of genomic regions, then subjected to sequencing. Each exome sequencing experiment yielded approximately 240 million mappable reads representing 12 billion base pairs. We used DiBayes to identify single nucleotide variants (SNVs). After filtering away the low-quality SNVs, we identified approximately 18,000 high-quality SNVs in each sample, of which ∼7500 are within the protein coding regions. Using the frequencies of the SNVs derived from the sequencing experiments, we discovered a shared LOH signature at the chromosome level among all three tumors indicating they originate from a common cancer progenitor. When we examined the germline DNA, we found about 97% of SNVs for each tumor sample were also found in the germline DNA, and each tumor had more than 300 unique somatic SNVs. These data showed that despite of the shared LOH pattern, tumor genomes are highly unstable at the single nucleotide level. Furthermore, we also found that the three tumor samples shared 64 SNVs which may be potential driver mutations. Twenty of those common 64 SNVs, located on 7 genes, are predicted to be damaging mutations by SIFT algorithm. These mutations are currently being validated using Sanger sequencing, and further RNA-seq in the same tumor samples to investigate for pathway disruption that may lead to chemo-refractory disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4833. doi:10.1158/1538-7445.AM2011-4833