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KRAS  mutation is a well‐known marker for poor response to targeted treatment and patient prognosis in microsatellite stable (MSS) colorectal cancer (CRC). However, variation in clinical outcomes among patients wild‐type for  KRAS  underlines that this is not a homogeneous population. Here, we evaluated the prognostic impact of  KRAS  alternative splicing in relation to mutation status in a single‐hospital series of primary MSS CRCs ( N  = 258). Using splicing‐sensitive microarrays and RNA sequencing, the relative expression of  KRAS‐4A  versus  KRAS‐4B  transcript variants was confirmed to be down‐regulated in CRC compared to normal colonic mucosa ( N  = 41;  p  ≤ 0.001). This was independent of mutation status, however, gene set enrichment analysis revealed that the effect of splicing on KRAS signaling was specific to the  KRAS  wild‐type subgroup, in which low relative  KRAS‐4A  expression was associated with a higher level of KRAS signaling ( p  = 0.005). In concordance, the prognostic value of  KRAS  splicing was also dependent on mutation status, and for patients with Stage I–III  KRAS  wild‐type MSS CRC, low relative  KRAS‐4A  expression was associated with inferior overall survival (HR: 2.36, 95% CI: 1.07–5.18,  p  = 0.033), a result not found in mutant cases ( p  interaction  = 0.026). The prognostic association in the wild‐type subgroup was independent of clinicopathological factors, including cancer stage in multivariable analysis (HR: 2.68, 95% CI: 1.18–6.09,  p  = 0.018). This suggests that  KRAS  has prognostic value beyond mutation status in MSS CRC, and highlights the importance of molecular heterogeneity in the clinically relevant  KRAS  wild‐type subgroup.

Alternative splicing expands the prognostic impact of KRAS in microsatellite stable primary colorectal cancer