Microsatellite Instability-Related ACVR2A Mutations Partially Account for Decreased Lymph Node Metastasis in MSI-H Gastric Cancers

• Main Authors: Zhao L, Zhang J, Qu X, Yang Y, Gong Z, Wu Z, Guo W
• Format: Article
• Language: English
• Published: Dove Medical Press 2020-05-01
• Series: OncoTargets and Therapy
• Subjects: microsatellite instability; activin a receptor type 2a; gene mutation; stomach neoplasms; neoplasm metastasis
• Online Access: https://www.dovepress.com/microsatellite-instability-related-acvr2a-mutations-partially-account--peer-reviewed-article-OTT

Liqin Zhao,1,2,* Jieyun Zhang,1,2,* Xiaofei Qu,2,3,* Ya’nan Yang,1,2 Zhe Gong,1,2 Yue Yang,1,2 Zhenhua Wu,1,2 Weijian Guo1,2 1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weijian GuoDepartment of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, People’s Republic of ChinaTel [phone]Fax [phone]Email [e-mail]: Gene mutations play important roles in tumour metastasis, which significantly affect the prognosis of gastric cancer (GC) patients. This study aimed to compare lymph node (LN) metastasis of GCs with different microsatellite instability (MSI) statuses and explore the effect of ACVR2A mutations on GC LN metastasis.Materials and Methods: The association between clinicopathologic characteristics and MSI status or ACVR2A mutational status was analysed based on a GC dataset from The Cancer Genome Atlas (TCGA). The association of ACVR2A mutations with MSI status was assessed. Whole-exome sequencing data of 157 GCs from Chinese patients at Fudan University Shanghai Cancer Center were used to validate the association of mutated ACVR2A and MSI status. Survival plots were obtained from the KMPlot and cBioPortal databases. The roles of ACVR2A and its common mutants in GC cell migration and proliferation were assayed in vitro.Results: LN metastasis was significantly decreased in MSI-H GCs compared with microsatellite instability-low or microsatellite stable (MSI-L/MSS) GCs (P=0.016). As the most frequently mutated gene in MSI-H GCs, mutated ACVR2A was significantly associated with MSI-H (P< 0.001) and a higher mutation frequency (P< 0.001). Additionally, a tendency toward decreased LN metastasis was observed in GCs with mutated ACVR2A, although the P value was not statistically significant (P=0.052). Higher expression of ACVR2A predicted a poor prognosis, but patients with ACVR2A mutations had slightly better disease-free survival. Two polyadenine microsatellite loci in the ACVR2A coding region were hotspot mutation sites. In vitro experiments demonstrated that wild-type ACVR2A promoted GC cell migration probably via the Snail/Slug-EMT pathway, while ACVR2A truncated mutants lost this function.Conclusion: MSI-H GCs had lower LN metastasis partially due to ACVR2A mutations. Mutated ACVR2A was significantly associated with MSI-H in GC, making it a potential biomarker that could be useful in choosing candidates for immunotherapy.Keywords: microsatellite instability, activin A receptor type 2A, gene mutation, stomach neoplasms, neoplasm metastasis