Abstract

In cancer research, the term epigenetics was used in the 1970s in its modern sense encompassing non‐genetic events modifying the chromatin state, mainly to oppose the emerging oncogene paradigm. However, starting from the establishment of this prominent concept, the importance of these epigenetic phenomena in cancer rarely led to questioning the causal role of genetic alterations. Only in the last 10 years, the accumulation of problematic data, better experimental technologies, and some ambitious models pushed the idea that epigenetics could be at least as important as genetics in early oncogenesis. Until this year, a direct demonstration of epigenetic oncogenesis was still lacking. Now, Parreno, Cavalli and colleagues, using a refined experimental model in the fruit fly Drosophila melanogaster, enforced the initiation of tumors solely by imposing a transient loss of Polycomb repression, leading to a purely epigenetic oncogenesis phenomenon. Despite a few caveats that we discuss, this pioneering work represents a major breakpoint in cancer research. We are led to consider the theoretical and conceptual implications on oncogenesis and to search for links between this artificial experimental model and naturally occurring processes, while revisiting cancer theories that were previously proposed as alternatives to the oncogene‐centered paradigm.