Abstract
Consensus molecular subtyping 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 that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the 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 with polymerase chain reaction‐based methodology. DNA copy number was assessed by low‐coverage DNA sequencing (n = 30) or array‐comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 ‘metabolic subtype’, which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the ‘MSI immune’ subtype. Eight adenomas (13%) were classified as the ‘canonical’ CMS2. No adenomas were classified as the ‘mesenchymal’ CMS4, consistent with the fact that adenomas lack invasion‐associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high‐risk adenomas were observed in CMS2. 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. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Colorectal cancer (CRC) is heterogeneous in its molecular characteristics and its treatment response
Classification of adenomas according to consensus molecular subtype (CMS) was achieved for 54 of 62 adenomas, in a group-wise analysis together with 59 CRCs from the study dataset and 556 The Cancer Genome Atlas (TCGA) CRC samples [15,36]
The results were validated in the independent series, in which 34 of 45 adenomas where classified with the same method; group-wise analysis including 36 CRCs from the same series and 566 CRCs from the reference dataset [3,29]
Summary
Colorectal cancer (CRC) is heterogeneous in its molecular characteristics and its treatment response. Stratifying CRC patients into biologically and clinically distinct subtypes, based on gene expression profiles, has been performed in many studies, with the common aim of improving clinical precision [1,2,3,4,5,6,7]. A consensus RNA expression-based classifier was produced that classifies CRCs into four CMS groups. CMS1 includes ∼14% of CRCs, and is associated with microsatellite instability (MSI), BRAF mutation, promoter hypermethylation, and immune infiltration. CMS2 is the most prevalent CRC subtype (37%) and shows the hallmarks of canonical CRC carcinogenesis, including activation of the Wnt and Myc pathways. 13% of CRCs are in CMS3, characterised by dysregulated metabolism and KRAS mutation. CMS4 (23%) is described as a mesenchymal, stroma-rich group, associated with poor prognosis [8]
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