KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition

Publication Date:
2018-12-15
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
Published by:
http://www.aacr.org/
_version_ 1836399105111228417
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