Dataset Information

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

ABSTRACT: Purpose: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.

SUBMITTER: Zhao L

PROVIDER: S-EPMC7211323 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Microsatellite Instability-Related <i>ACVR2A</i> Mutations Partially Account for Decreased Lymph Node Metastasis in MSI-H Gastric Cancers.

Zhao Liqin L Zhang Jieyun J Qu Xiaofei X Yang Ya'nan Y Gong Zhe Z Yang Yue Y Wu Zhenhua Z Guo Weijian W

OncoTargets and therapy 20200505

<h4>Purpose</h4>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 <i>ACVR2A</i> mutations on GC LN metastasis.<h4>Materials and methods</h4>The association between clinicopathologic characteristics and MSI status or <i>ACVR2A</i> mutational status was analysed based on a G ...[more]

PMID: 32440149

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Project description:Microsatellite DNA sequences display allele length alterations or microsatellite instability (MSI) in tumor tissues, and MSI is used diagnostically for tumor detection and classification. We discuss the known types of tumor-specific MSI patterns and the relevant mechanisms underlying each pattern. Mutation rates of individual microsatellites vary greatly, and the intrinsic DNA features of motif size, sequence, and length contribute to this variation. MSI is used for detecting mismatch repair (MMR)-deficient tumors, which display an MSI-high phenotype due to genome-wide microsatellite destabilization. Because several pathways maintain microsatellite stability, tumors that have undergone other events associated with moderate genome instability may display diagnostic MSI only at specific di- or tetranucleotide markers. We summarize evidence for such alternative MSI forms (A-MSI) in sporadic cancers, also referred to as MSI-low and EMAST. While the existence of A-MSI is not disputed, there is disagreement about the origin and pathologic significance of this phenomenon. Although ambiguities due to PCR methods may be a source, evidence exists for other mechanisms to explain tumor-specific A-MSI. Some portion of A-MSI tumors may result from random mutational events arising during neoplastic cell evolution. However, this mechanism fails to explain the specificity of A-MSI for di- and tetranucleotide instability. We present evidence supporting the alternative argument that some A-MSI tumors arise by a distinct genetic pathway, and give examples of DNA metabolic pathways that, when altered, may be responsible for instability at specific microsatellite motifs. Finally, we suggest that A-MSI in tumors could be molecular signatures of environmental influences and DNA damage. Importantly, A-MSI occurs in several pre-neoplastic inflammatory states, including inflammatory bowel diseases, consistent with a role of oxidative stress in A-MSI. Understanding the biochemical basis of A-MSI tumor phenotypes will advance the development of new diagnostic tools and positively impact the clinical management of individual cancers.

Dataset Information

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

Publications

Microsatellite Instability-Related <i>ACVR2A</i> Mutations Partially Account for Decreased Lymph Node Metastasis in MSI-H Gastric Cancers.

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