Alternative Splicing Expands the Prognostic Impact of KRAS in Microsatellite Stable Primary Colorectal Cancer

Int J Cancer. 2019 Feb 15;144(4):841-847. doi: 10.1002/ijc.31809. Epub 2018 Oct 30.

Abstract

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 (pinteraction = 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.

Keywords: KRAS; alternative splicing; colorectal cancer; microsatellite stable; prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alternative Splicing*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Disease-Free Survival
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • Mutation
  • Prognosis
  • Proto-Oncogene Proteins p21(ras) / genetics*

Substances

  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)