KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition
Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S.
The American Association for Cancer Research (AACR)
Published 2018
The American Association for Cancer Research (AACR)
Published 2018
Publication Date: |
2018-12-15
|
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Publisher: |
The American Association for Cancer Research (AACR)
|
Print ISSN: |
1078-0432
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Electronic ISSN: |
1557-3265
|
Topics: |
Medicine
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Published by: |
_version_ | 1836399105111228417 |
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autor | Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. |
beschreibung | Purpose: Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C ( KMT2C ) as a frequently mutated gene and examined its role in DGA progression. Experimental Design: We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C ( KMT2C ) was analyzed in DGA cell lines and in patient tumors. Results: KMT2C was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage ( P = 0.023) and worse overall survival ( P = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. Conclusions: KMT2C is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival. |
citation_standardnr | 6369738 |
datenlieferant | ipn_articles |
feed_id | 9363 |
feed_publisher | The American Association for Cancer Research (AACR) |
feed_publisher_url | http://www.aacr.org/ |
insertion_date | 2018-12-15 |
journaleissn | 1557-3265 |
journalissn | 1078-0432 |
publikationsjahr_anzeige | 2018 |
publikationsjahr_facette | 2018 |
publikationsjahr_intervall | 7984:2015-2019 |
publikationsjahr_sort | 2018 |
publisher | The American Association for Cancer Research (AACR) |
quelle | Clinical Cancer Research |
relation | http://clincancerres.aacrjournals.org/cgi/content/short/24/24/6556?rss=1 |
search_space | articles |
shingle_author_1 | Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. |
shingle_author_2 | Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. |
shingle_author_3 | Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. |
shingle_author_4 | Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. |
shingle_catch_all_1 | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition Purpose: Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C ( KMT2C ) as a frequently mutated gene and examined its role in DGA progression. Experimental Design: We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C ( KMT2C ) was analyzed in DGA cell lines and in patient tumors. Results: KMT2C was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage ( P = 0.023) and worse overall survival ( P = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. Conclusions: KMT2C is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival. Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. The American Association for Cancer Research (AACR) 1078-0432 10780432 1557-3265 15573265 |
shingle_catch_all_2 | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition Purpose: Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C ( KMT2C ) as a frequently mutated gene and examined its role in DGA progression. Experimental Design: We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C ( KMT2C ) was analyzed in DGA cell lines and in patient tumors. Results: KMT2C was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage ( P = 0.023) and worse overall survival ( P = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. Conclusions: KMT2C is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival. Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. The American Association for Cancer Research (AACR) 1078-0432 10780432 1557-3265 15573265 |
shingle_catch_all_3 | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition Purpose: Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C ( KMT2C ) as a frequently mutated gene and examined its role in DGA progression. Experimental Design: We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C ( KMT2C ) was analyzed in DGA cell lines and in patient tumors. Results: KMT2C was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage ( P = 0.023) and worse overall survival ( P = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. Conclusions: KMT2C is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival. Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. The American Association for Cancer Research (AACR) 1078-0432 10780432 1557-3265 15573265 |
shingle_catch_all_4 | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition Purpose: Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C ( KMT2C ) as a frequently mutated gene and examined its role in DGA progression. Experimental Design: We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C ( KMT2C ) was analyzed in DGA cell lines and in patient tumors. Results: KMT2C was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage ( P = 0.023) and worse overall survival ( P = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. Conclusions: KMT2C is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival. Cho, S.-J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-x., Kim, Y.-H., Kook, M.-C., Aksoy, B. A., Park, D. J., Ashktorab, H., Smoot, D. T., Schultz, N., Yoon, S. S. The American Association for Cancer Research (AACR) 1078-0432 10780432 1557-3265 15573265 |
shingle_title_1 | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition |
shingle_title_2 | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition |
shingle_title_3 | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition |
shingle_title_4 | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition |
timestamp | 2025-06-30T23:37:40.373Z |
titel | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition |
titel_suche | KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition |
topic | WW-YZ |
uid | ipn_articles_6369738 |