Clonal effects of the oncogene revealed by somatic mutagenesis in a cancer model.

Somatic mutations of , encoding a small GTPase, are detected in a wide range of human cancers. Tumor genome sequencing further reveals a cancer type-dependent mutational spectrum for the gene, suggesting that tissue- and allele-specific effects underlie tumorigenic activity. Although biochemical studies have characterized the GTPase activity of several Ras variants , precisely how somatic mutations of the endogenous locus differentially affect tissue growth and homeostasis remain elusive. Here we engineered the endogenous locus to create a spectrum of inducible oncogenic alleles and then compared their activities . In the developing wing primordium, somatic clones carrying the oncogenic mutation exhibited a weak activation of downstream MAPK signaling but did not disrupt tissue architecture. However, cell clones carrying the same allele in the adult midgut exhibited a growth advantage and progressively took over the tissue, resulting in intestinal barrier dysfunction. In contrast, cell clones expressing a distinct allele, , formed aberrant cysts that disrupted epithelial architecture and triggered local cell death. Conversely, when we induced cell clones carrying in the midgut, hyper-proliferating mutant cells rapidly expanded to occupy the entire tissue. Surprisingly, this population of rapidly expanding mutant cells was eventually eliminated from the midgut, restoring cells and normal barrier function. Thus, in the midgut, was ultimately more deleterious than due to the regression of mutant cells. These results establish a new model for somatic mutagenesis at the locus and illuminate a mechanistic basis for the tissue-specific effects of oncogenic variants. Further, this study provides direct evidence that allele-dependent clonal dynamics may play a critical role in the tissue-selectivity of oncogenic mutations.