SMAD4 and neoplasm: Intriguingly, this approach revealed that functional loss of the wild-type Apc allele was the most crucial event for tumor progression in Apcmin, KrasG12D and Tp53R172H tumors, but not in tumors that were initiated by heterozygous loss of Smad4. Instead, those tumors displayed frequent insertions in the wild-type Smad4 allele along with mutually exclusive insertions in Rspo1 and Rspo2 that promoted overexpression of these R-spondins, which are known enhancers of Wnt signaling.