Kizuki Yuza1, Masayuki Nagahashi2, Hiroshi Ichikawa1, Takaaki Hanyu1, Masato Nakajima1, Yoshifumi Shimada1, Takashi Ishikawa1, Jun Sakata1, Shiho Takeuchi3,4, Shujiro Okuda4, Yasunobu Matsuda5, Manabu Abe6, Kenji Sakimura6, Kazuaki Takabe1,7,8, Toshifumi Wakai1. 1. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. 2. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. mnagahashi@med.niigata-u.ac.jp. 3. Division of Cancer Genome Informatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. 4. Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. 5. Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Chuo-Ku, Niigata, Niigata, 951-8518, Japan. 6. Department of Animal Model Development, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8585, Japan. 7. Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. 8. Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, 14263, USA.
Abstract
BACKGROUND: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations. METHODS: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. One hundred twenty-four patients with gastric cancer were retrospectively analyzed, and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated. RESULTS: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration, and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival. CONCLUSIONS: Our study demonstrated that gastric cancer patients with ACVR2A mutation have a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors.
BACKGROUND: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations. METHODS: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. One hundred twenty-four patients with gastric cancer were retrospectively analyzed, and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated. RESULTS: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration, and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival. CONCLUSIONS: Our study demonstrated that gastric cancer patients with ACVR2A mutation have a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors.
Authors: Razvan Cristescu; Jeeyun Lee; Michael Nebozhyn; Kyoung-Mee Kim; Jason C Ting; Swee Seong Wong; Jiangang Liu; Yong Gang Yue; Jian Wang; Kun Yu; Xiang S Ye; In-Gu Do; Shawn Liu; Lara Gong; Jake Fu; Jason Gang Jin; Min Gew Choi; Tae Sung Sohn; Joon Ho Lee; Jae Moon Bae; Seung Tae Kim; Se Hoon Park; Insuk Sohn; Sin-Ho Jung; Patrick Tan; Ronghua Chen; James Hardwick; Won Ki Kang; Mark Ayers; Dai Hongyue; Christoph Reinhard; Andrey Loboda; Sung Kim; Amit Aggarwal Journal: Nat Med Date: 2015-04-20 Impact factor: 53.440
Authors: Elena Deacu; Yuriko Mori; Fumiaki Sato; Jing Yin; Andreea Olaru; Anca Sterian; Yan Xu; Suna Wang; Karsten Schulmann; Agnes Berki; Takatsugu Kan; John M Abraham; Stephen J Meltzer Journal: Cancer Res Date: 2004-11-01 Impact factor: 12.701
Authors: Paula M Hempen; Lin Zhang; Ravi K Bansal; Christine A Iacobuzio-Donahue; Kathleen M Murphy; Anirban Maitra; Bert Vogelstein; Robert H Whitehead; Sanford D Markowitz; James K V Willson; Charles J Yeo; Ralph H Hruban; Scott E Kern Journal: Cancer Res Date: 2003-03-01 Impact factor: 12.701
Authors: Yuriko Mori; Fumiaki Sato; Florin M Selaru; Andreea Olaru; Kellie Perry; Martha C Kimos; Gen Tamura; Nagahide Matsubara; Suna Wang; Yan Xu; Jing Yin; Tong-Tong Zou; Barbara Leggett; Joanne Young; Toshihiro Nukiwa; O Colin Stine; John M Abraham; David Shibata; Stephen J Meltzer Journal: Cancer Res Date: 2002-07-01 Impact factor: 12.701
Authors: Niranjan Nagarajan; Denis Bertrand; Axel M Hillmer; Zhi Jiang Zang; Fei Yao; Pierre-Étienne Jacques; Audrey S M Teo; Ioana Cutcutache; Zhenshui Zhang; Wah Heng Lee; Yee Yen Sia; Song Gao; Pramila N Ariyaratne; Andrea Ho; Xing Yi Woo; Lavanya Veeravali; Choon Kiat Ong; Niantao Deng; Kartiki V Desai; Chiea Chuen Khor; Martin L Hibberd; Atif Shahab; Jaideepraj Rao; Mengchu Wu; Ming Teh; Feng Zhu; Sze Yung Chin; Brendan Pang; Jimmy B Y So; Guillaume Bourque; Richie Soong; Wing-Kin Sung; Bin Tean Teh; Steven Rozen; Xiaoan Ruan; Khay Guan Yeoh; Patrick B O Tan; Yijun Ruan Journal: Genome Biol Date: 2012-12-13 Impact factor: 13.583
Authors: Jessica Bauer; Ozkan Ozden; Naomi Akagi; Timothy Carroll; Daniel R Principe; Jonas J Staudacher; Martina E Spehlmann; Lars Eckmann; Paul J Grippo; Barbara Jung Journal: Mol Cancer Date: 2015-10-24 Impact factor: 27.401