Peter W. Eide

Elevated miR‐31 expression is associated with poor outcome in colorectal cancer (CRC). Whether the prognostic information is independent of known molecular subgroups and gene expression‐based consensus molecular subtypes (CMS) is currently unknown. To investigate this, we analyzed nearly 2000 CRC biopsies and preclinical models. The expression of miR‐31‐5p and its host transcript, long noncoding RNA MIR31HG, was strongly correlated (Spearman's ρ > 0.80). MIR31HG outlier expression was observed in 158/1265 (12%) of pCRCs and was associated with depletion of CMS2‐canonical subgroup (odds ratio = 0.21 [0.11–0.35]) and shorter relapse‐free survival (RFS) in multivariable analysis (adjusted hazard ratio = 2.2 [1.6–3.0]). For stage II disease, 5‐year RFS for patients with MIR31HG outlier status was 49% compared to 77% for those with normal‐like expression. MIR31HG outlier status was associated with inferior outcome also within clinical high risk groups and within the poor prognostic CMS4‐mesenchymal gene expression subtype specifically. Preclinical models with MIR31HG outlier expression were characterized by reduced expression of MYC targets as well as elevated epithelial‐mesenchymal transition, TNF‐α/NFκB, TGF‐β, and IFN‐α/γ gene expression signatures, indicating cancer cell‐intrinsic properties resembling the CMS4 subgroup—associations which were recapitulated in patient biopsies. Moreover, the prognostic value of MIR31HG outlier status was independent of cytotoxic T lymphocyte and fibroblast infiltration. We here present evidence that MIR31HG expression provides clinical stratification beyond major gene expression phenotypes and tumor immune and stromal cell infiltration and propose a model where increased expression is an indicator of a cellular state conferring intrinsic invasive and/or immuno‐evasive capabilities.