Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas
The mechanism behind the pathogenesis and carcinogenesis of these neoplasms is not fully understood. The objective of this study was to identify genetic markers and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas through gene expression analysis.
Gene expression profiling was performed in 4 pairs of duodenal adenoma/adenocarcinomas and corresponding matched normal tissue. Genes with consistent expression differences were identified and confirmed in 7 independent pairs. Gene set enrichment analysis (GSEA) was performed to characterize gene expression profiles of duodenal adenoma/adenocarcinomas, together with immunohistochemical staining of candidate oncogenic genes.
626 probes consistently demonstrated over a twofold expression difference between tumor–normal pairs. Reverse transcriptase polymerase chain reaction of genes with the most prominent difference in expression between tumors and normal mucosa (KLK7, KLK6, CEMIP, MMP7, KRT17, LGR5, G6PC, S100G, APOA1) validated the results of gene expression analysis. GSEA demonstrated a strong association between duodenal adenoma/adenocarcinomas with colorectal adenomas (p < 10−5) and gene expression patterns seen after APC gene knockout (p < 10−5), suggesting that the Wnt/β-catenin pathway plays a crucial role in the carcinogenesis of these neoplasms. Immunohistochemical staining of an independent group of duodenal adenomas confirmed over-accumulation of β-catenin in 80.0% (16/20).
Precancerous duodenal adenomas and early stage adenocarcinomas demonstrate gene expression characteristics with a strong resemblance to colorectal adenomas. The results of this study strongly suggest that upregulation of the Wnt/β-catenin pathway is the major factor involved in the initial stages of the carcinogenesis of duodenal adenocarcinomas.
KeywordsDuodenal adenoma Duodenal adenocarcinoma Comprehensive gene expression analysis Wnt/β-catenin pathway Gene set enrichment analysis
The authors thank Shinya Kodashima, Satoshi Ono, Yosuke Tsuji, Keiko Niimi for their assistance as participating investigators in acquisition of samples, and Hironori Waki, Yuta Hiraike for their assistance in RNA extraction.
Conception and design: YS, NY, ST. Development of methodology: YS, NY, ST, CT, NKY, YT, KS, KI. Acquisition of data: YS, MI, MF. Analysis and interpretation of data: YS, NY, ST, CT, YT, KS, KI. Writing, review, and/or revision of the manuscript: YS, NY, ST, CT, NKY, YT, KK.
This work was supported in part by a research grant from the Japanese Foundation for Research and Promotion of Endoscopy, in part by Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science, and in part by Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.