Intratumor CMS Heterogeneity Impacts Patient Prognosis in Localized Colon Cancer

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2021 Jun 25

PMID 34168047

Citations 25

Authors

Laetitia Marisa

Yuna Blum

Julien Taieb

Mira Ayadi

Camilla Pilati

Karine Le Malicot

Come Lepage

Ramon Salazar

Daniela Aust

Alex Duval

Helene Blons

Valerie Taly

David Gentien

Audrey Rapinat

Janick Selves

Sophie Mouillet-Richard

Valerie Boige

Jean-Francois Emile

Aurelien De Reynies

Pierre Laurent-Puig

Affiliations

Soon will be listed here.

Abstract

Purpose: The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understanding its potential prognostic implications.

Experimental Design: We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned to each tumor and cell line a combination of up to three CMS subtypes with a threshold above 20%.

Results: Over 55% of tumors corresponded to mixtures of at least two CMSs, demonstrating pervasive ITH in colon cancer. Of note, ITH was associated with shorter disease-free survival (DFS) and overall survival, [HR, 1.34; 95% confidence interval (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 colon cancer cell lines are a mixture of cells falling into different CMSs, indicating that ITH may correspond to distinct functional statuses of colon cancer cells.

Conclusions: This study shows that CMS-based transcriptomic ITH is frequent in colon cancer and impacts its prognosis. CMS-based transcriptomic ITH may correspond to distinct functional statuses of colon cancer cells, suggesting plasticity between CMS-related cell populations. Transcriptomic ITH deserves further assessment in the context of personalized medicine.

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