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

Authors :
Daisuke Ohki
Nobutake Yamamichi
Yoshiki Sakaguchi
Yu Takahashi
Natsuko Kageyama-Yahara
Mitsue Yamamichi
Chihiro Takeuchi
Yosuke Tsuji
Yasuhiro Sakai
Kouhei Sakurai
Shuta Tomida
Kazuhiko Koike
Mitsuhiro Fujishiro
Source :
Cancer Medicine. Dec2022, Vol. 11 Issue 24, p5066-5078. 13p.
Publication Year :
2022

Abstract

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 tumornormal 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). [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20457634
Volume :
11
Issue :
24
Database :
Academic Search Index
Journal :
Cancer Medicine
Publication Type :
Academic Journal
Accession number :
161411445
Full Text :
https://doi.org/10.1002/cam4.4810