Through the use of a spatiotemporally controlled murine system targeting genomic alterations to a single pool of epithelial progenitor cells, we now show that unrestrained YAP activation in the context of TP53 and CDKN2A inhibition by HPV E6-E7 oncogenes induces carcinoma with rapid kinetics and nearly complete penetrance, enabling in-depth investigation of tumor initiation. Here, CDKN2A is linked to neoplasm.