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Comparative Study
. 2018 Nov;246(3):266-276.
doi: 10.1002/path.5129. Epub 2018 Aug 31.

Consensus molecular subtype classification of colorectal adenomas

Malgorzata A Komor  1   2 , Linda Jw Bosch  1 , Gergana Bounova  3 , Anne S Bolijn  1 , Pien M Delis-van Diemen  1 , Christian Rausch  1 , Youri Hoogstrate  4 , Andrew P Stubbs  5 , Mark de Jong  6 , Guido Jenster  4 , Nicole Ct van Grieken  7 , Beatriz Carvalho  1 , Lodewyk Fa Wessels  3   8 , Connie R Jimenez  2 , Remond Ja Fijneman  1 , Gerrit A Meijer  1 ; NGS-ProToCol Consortium:
Collaborators, Affiliations
Comparative Study

Consensus molecular subtype classification of colorectal adenomas

Malgorzata A Komor et al. J Pathol. 2018 Nov.

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.

Keywords: adenoma; colon; colorectal cancer; neoplasia; rectum.

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Figures

Figure 1
Figure 1
Overview of the data analysis approach. Both Series 1 and Series 2 were normalised separately to the TCGA CRC dataset via a batch effect removal method 27. After normalisation, all three datasets were merged together. Series 1 and Series 2 form the ‘study dataset’. CMS classification was applied to the merged dataset. The classes were obtained with the CMS random forest classifier, and assigned when the posterior probability of belonging to a CMS class was ≥0.5. Results of the classification were extracted for the CRCs and the adenomas from the study dataset. The pie charts represent the distribution of CMS classes for CRCs (left) and adenomas (right) for the study dataset.
Figure 2
Figure 2
Hierarchical clustering based on gene expression profiles of the top 30 most variable genes. (A) Heatmap of all three datasets before batch effect removal. The batches corresponding to the TCGA dataset, Series 1 and Series 2 can be distinguished in the heatmap. (B) Heatmap before batch correction of the Series 1 and Series 2 study datasets only. Within the two batches, one can distinguish clusters enriched with adenomas and clusters enriched with cancers. (C) Heatmap of all three datasets after batch effect removal. Samples from the three experiments do not cluster together. (D) Heatmap of the Series 1 and Series 2 study datasets after batch effect removal. Clusters enriched with adenomas or cancers can still be distinguished, meaning that batch effect correction did not remove the variability between different lesions. The legend corresponds to all of the heatmaps in this figure.
Figure 3
Figure 3
Distribution of CMS classes among adenomas at high risk and adenomas at low risk of progressing to cancer. (A) Distribution of CMS classes among 13 high‐risk adenomas. (B) Distribution of CMS classes among 39 low‐risk adenomas. No high‐risk and low‐risk adenomas were classified as CMS1 or CMS4.
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