Background
Somatic mutations can be grouped into 96 tri-nucleotide patterns, termed mutational signatures. These signatures can provide insights into underlying processes that fuel the evolution of tumor cells, and may expose therapeutic intervention avenues. Here we investigated the mutational signature of 84 whole genome sequenced neuroblastoma cases.
Results
Mutational signature analysis revealed an extreme bias towards Cytosine to Adenine (CtoA) mutations in a subset of tumors. This seems to be a unique feature of neuroblastoma. CtoA mutations are primarily found in high stage tumors and are therefore associated with a poor prognosis. Oxidative stress is known to be a source for such mutations, which can accumulate due to defects in the 8-Oxo-Guanine repair pathway genes OGG1, MUTYH and MTH1. We could show a strong correlation between CtoA mutations and chromosomal loss of OGG1, MUTYH. Besides copy number losses, sequencing also revealed a tumor with a homozygous inactivation of OGG1 and this tumor showed a very strong bias towards CtoA mutations. We could show that neuroblastoma cell lines with loss of either OGG1, MUTYH, or both, had higher 8-Oxo-Guanine content than cell lines without these losses. 8-Oxo-Guanine content is also correlated with CtoA mutation frequency in short term cultured neuroblastoma organoids. Overexpression of OGG1 in neuroblastoma cell lines with losses of OGG1 leads to rescue of the phenotype and a decrease in the amount of 8-Oxo-Guanine in the DNA. We are currently testing the efficacy of compounds that further interfere in this specific branch of DNA damage repair including the newly developed MTH1 inhibitors.
Conclusion
We identified a subset of neuroblastoma tumors with a high CtoA mutation frequency, which correlates with losses of glycosylases involved in the repair of CtoA mutations. 8-Oxo-guanine levels are elevated in cell lines with loss of OGG1, which can be rescued by overexpression of OGG1.