Frank, S. A. 2026. Cancer initiation: breaching developmental barriers. Trends Open (in press)

Cancer is commonly understood to arise from oncogenic mutations that stimulate proliferation or tumor-suppressor mutations that remove constraints on cell division or survival. However, I show that ten of the most frequently mutated cancer genes (TP53, PIK3CA, KRAS, APC, KMT2C, KMT2D, BRAF, ARID1A, PTEN, and CDKN2A) in their normal function either maintain cellular lineage identity or enforce terminal differentiation. I argue that the primary mechanism of cancer initiation arises when perturbations to these genes breach developmental barriers, releasing the plasticity characteristic of development. Proliferation follows from the less differentiated state rather than acting as the initiating event. This perspective reframes oncogene and tumor-suppressor classifications by placing loss of developmental constraint at the center of tumor initiation.