Intratumor CMS Heterogeneity Impacts Patient Prognosis in Localized Colon Cancer
Résumé
PURPOSE: The consensus molecular subtypes (CMS) represent a significant advance in the understanding of inter-tumor heterogeneity in colon cancer (CC). Intra-tumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of CC and understanding its potential prognostic implications Experimental Design: We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 CC cell lines as weighted sums of the 4 CMS, using the WISP algorithm. We assigned to each tumor and cell line a combination of up to 3 CMS subtypes with a threshold above 20%. RESULTS: Over 55% of tumors corresponded to mixtures of at least two CMS, demonstrating pervasive ITH in CC. Of note, ITH was associated with shorter disease-free survival (DFS) and overall survival (OS), (hazard ratio 1.34, 95%CI [1.12-1.59], 1.40, 95%CI [1.14-1.71] respectively). Moreover, we uncovered specific combinations of CMS associated with dismal prognosis. In multivariate analysis, ITH represents the third parameter explaining DFS variance, after T and N stages. At a cellular level, combined WISP and single-cell transcriptomic analysis revealed that most CC cell lines are mixture of cells falling into different CMS, indicating that ITH may correspond to distinct functional statuses of CC cells. CONCLUSIONS: This study shows that CMS-based transcriptomic ITH is frequent in CC and impacts its prognosis. CMS-based transcriptomic ITH may correspond to distinct functional statuses of CC cells suggesting plasticity between CMS-related cell populations. Transcriptomic ITH deserves further assessment in the context of personalized medicine.
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