Overlapping and Distinct Transcriptional Functions of an Extended Repertoire of KRAS Mutations

The challenge of interpreting novel genetic variations in genomics is widespread. Previous studies have shown the role of KRAS mutations in heritable and somatic conditions, but more genetic variants have been observed than have been characterized. This study compares a broad genomic landscape of 25 KRAS mutations at three cellular checkpoint levels: ERK and AKT signaling, early cell-intrinsic transcriptional regulation, and secretory inflammatory responses. The results show heterogeneity in KRAS biology, with distinct mutations inducing significantly different levels of phosphorylated ERK, transcriptional profiles, and cytokine protein profiles. This heterogeneity may underlie variation in inter-individual disease patterns and contribute to differences in disease initiation or progression. Transcriptional profiles implicate different extents of feedback from upstream receptor kinases through diverse downstream nuclear targets and immunomodulatory programs. Integrated analysis reveals heterogeneity and potentially actionable outcomes for distinct groups of KRAS mutations in human cells.