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Activin a Receptor Type 2A Mutation Affects the Tumor Biology of Microsatellite Instability-High Gastric Cancer
Kizuki Yuza1, Masayuki Nagahashi2, Hiroshi Ichikawa1
1Division 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.
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.
Insights
Microsatellite instability-high (MSI-H) gastric cancer patients with ACVR2A mutations show a better prognosis. ACVR2A gene dysfunction in MSI-H gastric cancer cells reduces tumor aggressiveness, highlighting its role in tumor progression.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Activin A receptor type 2A (ACVR2A) is frequently mutated in microsatellite instability-high (MSI-H) gastric cancer.
- The clinical significance of ACVR2A mutations in MSI-H gastric cancer remains largely unknown.
- This study investigates the impact of ACVR2A mutations on tumor behavior and patient characteristics.
Purpose of the Study:
- To explore the effect of ACVR2A mutation on tumor biology in MSI-H gastric cancer.
- To identify clinicopathological characteristics associated with ACVR2A mutations in gastric cancer patients.
- To evaluate the prognostic value of ACVR2A mutations in gastric cancer.
Main Methods:
- In vitro study using CRISPR/Cas9 to knockout ACVR2A in MKN74 gastric cancer cells.
- Retrospective analysis of 124 gastric cancer patients.
- Evaluation of correlations between MSI status, ACVR2A mutations, and clinicopathological factors.
Main Results:
- ACVR2A knockout cells exhibited reduced proliferation, migration, and invasion.
- ACVR2A mutations were present in 8.1% of patients and exclusively in MSI-H cases (10/124).
- Patients with ACVR2A mutations had significantly higher 5-year overall survival rates (90%) compared to wild-type (57%).
- ACVR2A wild-type status, older age, and distant metastasis were independent negative prognostic factors.
Conclusions:
- Gastric cancer patients with ACVR2A mutations demonstrate a significantly better prognosis.
- ACVR2A dysfunction leads to less aggressive tumor biology in MSI-H gastric cancer.
- ACVR2A plays a critical role in the progression of MSI-H gastric tumors.
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