Transcriptome of sessile serrated adenoma/polyps is associated with <scp>MSI</scp>‐high colorectal cancer and decreased expression of <scp>CDX2</scp>

Yamamichi, Nobutake

doi:10.1002/cam4.4810

Cited by 5 publications

(1 citation statement)

References 40 publications

(120 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prior research has demonstrated that the biological differences between CMS subtypes are already installed at the premalignant state. For instance, CMS1 and CMS4 expression patterns have been linked to SSLs [17][18][19], while the majority of sporadic and hereditary conventional adenomas have been linked to expression patterns observed in the epithelial subtypes CMS3 and partly also CMS2 [18,20,21]. Although CMS3 was established as the main precursor CMS subtype, CMS2 was linked to precursor lesions at higher risk of malignant transformation [20].…”

Section: Introductionmentioning

confidence: 99%

Consensus molecular subtype transition during progression of colorectal cancer

van de Weerd,

Torang,

Zwager

et al. 2023

The Journal of Pathology

View full text Add to dashboard Cite

The consensus molecular subtype (CMS) classification divides colorectal cancer (CRC) into four distinct subtypes based on RNA expression profiles. The biological differences between CMSs are already present in CRC precursor lesions, but not all CMSs pose the same risk of malignant transformation. To fully understand the path to malignant transformation and to determine whether CMS is a fixed entity during progression, genomic and transcriptomic data from two regions of the same CRC lesion were compared: the precursor region and the carcinoma region. In total, 24 patients who underwent endoscopic removal of T1–2 CRC were included. Regions were subtyped for CMS and DNA mutation analysis was performed. Additionally, a set of 85 benign adenomas was CMS‐subtyped. This analysis revealed that almost all benign adenomas were classified as CMS3 (91.8%). In contrast, CMS2 was the most prevalent subtype in precursor regions (66.7%), followed by CMS3 (29.2%). CMS4 was absent in precursor lesions and originated at the carcinoma stage. Importantly, CMS switching occurred in a substantial number of cases and almost all (six out of seven) CMS3 precursor regions showed a shift to a different subtype in the carcinoma part of the lesion, which in four cases was classified as CMS4. In conclusion, our data indicate that CMS3 is related to a more indolent type of precursor lesion that less likely progresses to CRC and when this occurs, it is often associated with a subtype change that includes the more aggressive mesenchymal CMS4. In contrast, an acquired CMS2 signature appeared to be rather fixed during early CRC development. Combined, our data show that subtype changes occur during progression and that CMS3 switching is related to changes in the genomic background through acquisition of a novel driver mutation (TP53) or selective expansion of a clone, but also occurred independently of such genetic changes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

show abstract

Section: Introductionmentioning

confidence: 99%

Consensus molecular subtype transition during progression of colorectal cancer

van de Weerd,

Torang,

Zwager

et al. 2023

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

Transcriptome of sessile serrated adenoma/polyps is associated with MSI‐high colorectal cancer and decreased expression of CDX2

Yamamichi

2022

Cancer Medicine

View full text Add to dashboard Cite

The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor‐normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability‐high (MSI‐H) CRC (p < 10−5). Transcriptome analysis of five MSI‐related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC‐related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI‐H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis. (UMIN000027365).

show abstract