KRAS oncogenic mutations in benign tumors: adenomatoid odontogenic tumor as a model

The KRAS protein is a GTPase that plays a role in the MAPK/ERK signaling pathway and KRAS is one of the most frequently mutated proto-oncogenes in malignant neoplasms, including aggressive tumors such as lung, pancreatic, and colorectal cancer. Mutations in KRAS, previously considered oncogenic drivers and hallmarks of cancer, have been observed at a high frequency in benign sporadic tumors, including those with negligible potential for malignant transformation. In line with that, KRAS mutations have recently been shown to be highly prevalent in adenomatoid odontogenic tumor (AOT). In the present paper, we review the spectrum of KRAS mutations reported in AOT to date and discuss the context dependence of KRAS oncogenicity. KRAS p.G12V and p.G12R mutations have been reported in approximately 70 % of AOT cases. The fact that the same spectrum of KRAS mutations is found in tumors with diverse clinical behavior reinforces the tissue and context specificity of KRAS mutation effects. Genome-wide-based future studies may provide clarification on the molecular pathogenesis of the KRAS wild-type cases, and could potentially unravel additional genetic events in mutation-positive cases. In this scenario, the clarification of the molecular pathogenesis of AOT, a benign tumor of indolent behavior, sheds light into how KRAS oncogenic mutations exert distinct effects depending on the biological context.