Year: 2021
Type: article
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.
Source: Clinical Cancer Research
Authors: Laetitia Marisa, Yuna Blum, Julien Taieb, Mira Ayadi, Camilla Pilati, Karine Le Malicot, Côme Lepage, Ramon Salazar, Daniela Aust, Alex Duval, Hélène Blons, Valérie Taly, David Gentien, Audrey Rapinat, Janick Selves, Sophie Mouillet-Richard, Valérie Boige, Jean-François Emile, Aurélien de Reyniès, Pierre Laurent-Puig
Institutions: La Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Centre de Recherche des Cordeliers, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Université de Bourgogne, Fédération Francophone de Cancérologie Digestive, CHU Dijon Bourgogne, Institut d'Investigació Biomédica de Bellvitge, Institut Català d'Oncologia, Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, University Hospital Carl Gustav Carus, Centre de Recherche Saint-Antoine, Université Paris Sciences et Lettres, Université Toulouse III - Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, Centre de Recherches en Cancérologie de Toulouse, Université Paris-Saclay, Institut Gustave Roussy, Hôpital Ambroise-Paré
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Award: Immuno-Oncology
OpenAlex ID: W3174644591