Consensus molecular subtypes classification of colorectal adenomas

• Published in: The Journal of pathology 2018-07
• Main Authors: Komor, Malgorzata A, Bosch, Linda Jw, Bounova, Gergana, Bolijn, Anne S, van-Diemen, Pien Delis, Rausch, Christian, Hoogstrate, Youri, Stubbs, Andrew P, de Jong, Mark, Jenster, Guido, van Grieken, Nicole Ct, Carvalho, Beatriz, Wessels, Lodewyk Fa, Jimenez, Connie R, Fijneman, Remond Ja, Meijer, Gerrit A, Dits, Natasja, Böttcher, René, Hiemstra, Annemieke C, Ylstra, Bauke, Sie, Daoud, van den Broek, Evert, van der Meer, David, Pepers, Floor, Caldenhoven, Eric, Janssen, Bart, van Workum, Wilbert, van Lieshout, Stef, Bangma, Chris H, van Leenders, Geert, van de Werken, Harmen
• Format: Article
• Language: English
• ISSN: 1096-9896
• DOI: 10.1002/path.5129

Consensus molecular subtyping (CMS) is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA-expression. Only a minority of adenomas progress to malignancies, a transition associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into CMS classes, and whether specific CMS classes are related to presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined by PCR-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridization (n = 32). Adenomas were classified into CMS subtypes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), using the established CMS classifier. As a result, 54 out of 62 (87%) adenomas were classified according to the CMS. The CMS3 'metabolic subtype', least common among CRCs, was most prevalent among the adenomas (n = 45; 73%). One of the two adenomas exhibiting MSI was classified as CMS1 (2%), the 'MSI immune' subtype. Eight adenomas (13%) were classified as the 'canonical' CMS2 type. No adenomas were classified as the 'mesenchymal' CMS4 subtype, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. The CMS3 class was enriched with adenomas at low risk of progressing to CRC, while relatively more high-risk adenomas were observed in the CMS2 subtype. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC. This article is protected by copyright. All rights reserved.