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.
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.
J Gastrointest Surg. 2021 Sep;25(9):2231-2241. doi: 10.1007/s11605-020-04889-9. Epub 2021 Jan 8.
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.
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.
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.
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.
激活素 A 受体 2A（ACVR2A）是微卫星不稳定高（MSI-H）胃癌中最常突变的基因之一。然而，ACVR2A 突变在 MSI-H 胃癌患者中的临床相关性尚不清楚。本研究旨在探讨 ACVR2A 突变对肿瘤行为的影响，并确定携带 ACVR2A 突变的胃癌患者的临床病理特征。
通过 CRISPR/Cas9 介导的 ACVR2A 敲除 MKN74 人胃癌细胞进行体外研究，探讨 ACVR2A 的生物学作用。回顾性分析 124 例胃癌患者，评估 MSI 状态、ACVR2A 突变与临床病理因素的关系。
ACVR2A 敲除细胞的肿瘤生物学行为较 mock 转染细胞更具侵袭性，表现为增殖、迁移和侵袭减少（P<0.05）。10%（13/124）的胃癌患者存在 MSI 突变，8.1%（10/124）的患者存在 ACVR2A 突变。所有 ACVR2A 突变均伴有 MSI。ACVR2A 野生型患者和 ACVR2A 突变型患者的 5 年总生存率分别为 57%和 90%（P=0.048）。多因素分析显示，年龄较大（P=0.015）、远处转移（P<0.001）和 ACVR2A 野生型状态（P=0.040）是总生存的独立预后因素。
本研究表明，携带 ACVR2A 突变的胃癌患者的预后明显优于不携带 ACVR2A 突变的患者。在 MKN74 人胃癌细胞中，ACVR2A 功能失调导致肿瘤生物学行为更具侵袭性，提示 ACVR2A 在 MSI-H 肿瘤进展中的重要性。
