Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis

Byung Hoon Min; Jinha Hwang; Nayoung K.D. Kim; Gibeom Park; So Young Kang; Sangjeong Ahn; Soomin Ahn; Sang Yun Ha; Yun Kyung Lee; Ryoji Kushima; Michael Van Vrancken; Min Jung Kim; Changho Park; Ha Young Park; Jeesoo Chae; Se Song Jang; Sung Jin Kim; Young Ho Kim; Jong Il Kim; Kyoung Mee Kim

doi:10.1002/path.4777

Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis

Byung Hoon Min, Jinha Hwang, Nayoung K.D. Kim, Gibeom Park, So Young Kang, Sangjeong Ahn, Soomin Ahn, Sang Yun Ha, Yun Kyung Lee, Ryoji Kushima, Michael Van Vrancken, Min Jung Kim, Changho Park, Ha Young Park, Jeesoo Chae, Se Song Jang, Sung Jin Kim, Young Ho Kim, Jong Il Kim, Kyoung Mee Kim

Department of Physiology

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

Abstract

Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents.

Original language	English
Pages (from-to)	304-314
Number of pages	11
Journal	Journal of Pathology
Volume	240
Issue number	3
DOIs	https://doi.org/10.1002/path.4777
State	Published - 1 Nov 2016

Bibliographical note

Publisher Copyright:
Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords

dysplasia
high-throughput nucleotide sequencing
stomach cancer
transcriptome

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/path.4777

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Min, B. H., Hwang, J., Kim, N. K. D., Park, G., Kang, S. Y., Ahn, S., Ahn, S., Ha, S. Y., Lee, Y. K., Kushima, R., Van Vrancken, M., Kim, M. J., Park, C., Park, H. Y., Chae, J., Jang, S. S., Kim, S. J., Kim, Y. H., Kim, J. I., & Kim, K. M. (2016). Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis. Journal of Pathology, 240(3), 304-314. https://doi.org/10.1002/path.4777

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title = "Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis",

abstract = "Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents.",

keywords = "dysplasia, high-throughput nucleotide sequencing, stomach cancer, transcriptome",

author = "Min, {Byung Hoon} and Jinha Hwang and Kim, {Nayoung K.D.} and Gibeom Park and Kang, {So Young} and Sangjeong Ahn and Soomin Ahn and Ha, {Sang Yun} and Lee, {Yun Kyung} and Ryoji Kushima and {Van Vrancken}, Michael and Kim, {Min Jung} and Changho Park and Park, {Ha Young} and Jeesoo Chae and Jang, {Se Song} and Kim, {Sung Jin} and Kim, {Young Ho} and Kim, {Jong Il} and Kim, {Kyoung Mee}",

note = "Publisher Copyright: Copyright {\textcopyright} 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

year = "2016",

month = nov,

day = "1",

doi = "10.1002/path.4777",

language = "English",

volume = "240",

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Min, BH, Hwang, J, Kim, NKD, Park, G, Kang, SY, Ahn, S, Ahn, S, Ha, SY, Lee, YK, Kushima, R, Van Vrancken, M, Kim, MJ, Park, C, Park, HY, Chae, J, Jang, SS, Kim, SJ, Kim, YH, Kim, JI & Kim, KM 2016, 'Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis', Journal of Pathology, vol. 240, no. 3, pp. 304-314. https://doi.org/10.1002/path.4777

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T1 - Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis

AU - Min, Byung Hoon

AU - Hwang, Jinha

AU - Kim, Nayoung K.D.

AU - Park, Gibeom

AU - Kang, So Young

AU - Ahn, Sangjeong

AU - Ahn, Soomin

AU - Ha, Sang Yun

AU - Lee, Yun Kyung

AU - Kushima, Ryoji

AU - Van Vrancken, Michael

AU - Kim, Min Jung

AU - Park, Changho

AU - Park, Ha Young

AU - Chae, Jeesoo

AU - Jang, Se Song

AU - Kim, Sung Jin

AU - Kim, Young Ho

AU - Kim, Jong Il

AU - Kim, Kyoung Mee

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents.

AB - Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents.

KW - dysplasia

KW - high-throughput nucleotide sequencing

KW - stomach cancer

KW - transcriptome

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ER -

Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis

Abstract

Bibliographical note

Keywords

UN SDGs

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