Evolution and genomic signatures of spontaneous somatic mutation in Drosophila intestinal stem cells.

Abstract

Spontaneous mutations can alter tissue dynamics and lead to cancer initiation. Although large-scale sequencing projects have illuminated processes that influence somatic mutation and subsequent tumor evolution, the mutational dynamics operating in the very early stages of cancer development are currently not well understood. To explore mutational processes in the early stages of cancer evolution, we exploited neoplasia arising spontaneously in the Drosophila intestine. Analysing whole-genome sequencing data with a dedicated bioinformatic pipeline, we found neoplasia formation to be driven largely through the inactivation of Notch by structural variants, many of which involve highly complex genomic rearrangements. The genome-wide mutational burden in neoplasia was found to be similar to that of several human cancers. Finally, we identified genomic features associated with spontaneous mutation, and defined the evolutionary dynamics and mutational landscape operating within intestinal neoplasia over the short lifespan of the adult fly. Our findings provide unique insight into mutational dynamics operating over a short timescale in the genetic model system, Drosophila melanogaster.