Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas

Yoshiki Sakaguchi, Nobutake Yamamichi, Shuta Tomida, Chihiro Takeuchi, Natsuko Kageyama-Yahara, Yu Takahashi, Kazuya Shiogama, Ken ichi Inada, Masao Ichinose, Mitsuhiro Fujishiro, Kazuhiko Koike

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Abstract

Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Original languageEnglish
Pages (from-to)131-140
Number of pages10
JournalJournal of Gastroenterology
Volume54
Issue number2
DOIs
Publication statusPublished - 15-02-2019

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Adenoma
Adenocarcinoma
Catenins
Genes
Gene Expression
Carcinogenesis
Wnt Signaling Pathway
Staining and Labeling
APC Genes
Neoplasms
Gene Knockout Techniques
Gene Expression Profiling
Reverse Transcriptase Polymerase Chain Reaction
Genetic Markers
Transcriptome
Mucous Membrane
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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Sakaguchi, Y., Yamamichi, N., Tomida, S., Takeuchi, C., Kageyama-Yahara, N., Takahashi, Y., ... Koike, K. (2019). Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas. Journal of Gastroenterology, 54(2), 131-140. https://doi.org/10.1007/s00535-018-1489-4
Sakaguchi, Yoshiki ; Yamamichi, Nobutake ; Tomida, Shuta ; Takeuchi, Chihiro ; Kageyama-Yahara, Natsuko ; Takahashi, Yu ; Shiogama, Kazuya ; Inada, Ken ichi ; Ichinose, Masao ; Fujishiro, Mitsuhiro ; Koike, Kazuhiko. / Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas. In: Journal of Gastroenterology. 2019 ; Vol. 54, No. 2. pp. 131-140.
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abstract = "Background: 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. Methods: 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. Results: 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). Conclusions: 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.",
author = "Yoshiki Sakaguchi and Nobutake Yamamichi and Shuta Tomida and Chihiro Takeuchi and Natsuko Kageyama-Yahara and Yu Takahashi and Kazuya Shiogama and Inada, {Ken ichi} and Masao Ichinose and Mitsuhiro Fujishiro and Kazuhiko Koike",
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Sakaguchi, Y, Yamamichi, N, Tomida, S, Takeuchi, C, Kageyama-Yahara, N, Takahashi, Y, Shiogama, K, Inada, KI, Ichinose, M, Fujishiro, M & Koike, K 2019, 'Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas', Journal of Gastroenterology, vol. 54, no. 2, pp. 131-140. https://doi.org/10.1007/s00535-018-1489-4

Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas. / Sakaguchi, Yoshiki; Yamamichi, Nobutake; Tomida, Shuta; Takeuchi, Chihiro; Kageyama-Yahara, Natsuko; Takahashi, Yu; Shiogama, Kazuya; Inada, Ken ichi; Ichinose, Masao; Fujishiro, Mitsuhiro; Koike, Kazuhiko.

In: Journal of Gastroenterology, Vol. 54, No. 2, 15.02.2019, p. 131-140.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas

AU - Sakaguchi, Yoshiki

AU - Yamamichi, Nobutake

AU - Tomida, Shuta

AU - Takeuchi, Chihiro

AU - Kageyama-Yahara, Natsuko

AU - Takahashi, Yu

AU - Shiogama, Kazuya

AU - Inada, Ken ichi

AU - Ichinose, Masao

AU - Fujishiro, Mitsuhiro

AU - Koike, Kazuhiko

PY - 2019/2/15

Y1 - 2019/2/15

N2 - Background: 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. Methods: 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. Results: 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). Conclusions: 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.

AB - Background: 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. Methods: 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. Results: 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). Conclusions: 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.

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