This was demonstrated experimentally using sequential CRISPR/Cas guided knockout of the adenomatous polyposis coli (APC) gene, tumor protein p53 (TP53) gene, Kirsten rat sarcoma virus (KRAS) gene, and SMAD family member 4 (SMAD4) gene in intestinal stem cells resulting in mutant tumors with invasive carcinoma when xeno-transplanted into mice [17]. Here, SMAD4 is linked to invasive carcinoma.