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The consensus molecular subtype (CMS) classification divides colon tumors into four subtypes holding promise as a predictive biomarker. However, the effect of adjuvant chemotherapy on recurrence free survival (RFS) per CMS in stage III patients remains inadequately explored. With this intention, we selected stage III colon cancer (CC) patients from the MATCH cohort (n = 575) and RadboudUMC (n = 276) diagnosed between 2005 and 2018. Patients treated with and without adjuvant chemotherapy were matched based on tumor location, T‐ and N‐stage (n = 522). Tumor material was available for 464 patients, with successful RNA extraction and CMS subtyping achieved in 390 patients (surgery alone group: 192, adjuvant chemotherapy group: 198). In the overall cohort, CMS4 was associated with poorest prognosis (HR 1.55; p =.03). Multivariate analysis revealed favorable RFS for the adjuvant chemotherapy group in CMS1, CMS2, and CMS4 tumors (HR 0.19; p =.01, HR 0.27; p <.01, HR 0.19; p <.01, respectively), while no significant difference between treatment groups was observed within CMS3 (HR 0.68; p =.51). CMS subtyping in this non‐randomized cohort identified patients with poor prognosis and patients who may not benefit significantly from adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Gene signatures derived from cancer stem cells (CSCs) predict tumor recurrence for many forms of cancer. Here, we derived a gene signature for cobrectal CSCs defined by high Wnt signaling activity, which in agreement with previous observations predicts poor prognosis. Surprisingly, however, we found that elevated expression of Wnt targets was actually associated with good prognosis, while patient tumors with low expression of Wnt target genes segregated with immature stem cell signatures. We discovered that several Wnt target genes, including ASCL2 and LGR5, become silenced by CpG island methylation during progression of tumorigenesis, and that their re-expression was associated with reduced tumor growth. Taken together, our data show that promoter methylation of Wnt target genes is a strong predictor for recurrence of colorectal cancer, and suggest that CSC gene signatures, rather than reflecting CSC numbers, may reflect differentiation status of the malignant tissue. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a significant contributor to cancer‐related mortality, emphasizing the need for advanced biomarkers to guide treatment. As part of an international consortium, we previously categorized CRCs into four consensus molecular subtypes (CMS1‐CMS4), showing promise for outcome prediction. To facilitate clinical integration of CMS classification in settings where formalin‐fixed paraffin‐embedded (FFPE) samples are routinely used, we developed NanoCMSer, a NanoString‐based CMS classifier using 55 genes. NanoCMSer achieved high accuracy rates, with 95% for fresh‐frozen samples from the MATCH cohort and 92% for FFPE samples from the CODE cohort, marking the highest reported accuracy for FFPE tissues to date. Additionally, it demonstrated 96% accuracy across a comprehensive collection of 23 RNAseq‐based datasets, compiled in this study, surpassing the performance of existing models. Classifying with only 55 genes, the CMS predictions were still biologically relevant, recognizing CMS‐specific biology upon enrichment analysis. Additionally, we observed substantial differences in recurrence‐free survival curves when comparing CMS2/3 patients in stage III versus II. Probability of recurrence after 5 years increased by 21% in CMS2 and 31% in CMS3 for patients in stage III, whereas this difference was less pronounced for CMS1 and CMS4, with 11% and 10%, respectively. We posit NanoCMSer as a robust tool for subtyping CRCs for both tumor biology and clinical practice, accessible via nanocmser r package (https://github.com/LEXORlab/NanoCMSer) and Shinyapp (https://atorang.shinyapps.io/NanoCMSer). [ABSTRACT FROM AUTHOR]