Somatic alterations and mutational burden are potential predictive factors for metachronous development of early gastric cancer

Abstract

The risk of developing metachronous gastric cancer (MGC) following curative endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) remains even after eradicating Helicobacter pylori (HP) successfully. We screened initial EGC and adjacent non-cancerous mucosa ESD-resected specimens for somatic variants of 409 cancer-related genes, assessing their mutational burden (MB) to predict molecular markers for metachronous post-ESD development. We compared variants between ten patients diagnosed with MGC more than 3 years after ESD and ten age-matched patients who did not have MGC developments after successful HP eradication. We found no significant background differences between the two groups. In adjacent non-cancerous mucosa, the MB tended to be higher in the patients with metachronous developments than in the others. Somatic genomic alterations of RECQL4, JAK3, ARID1A, and MAGI1 genes were significantly associated with MGC development. The criteria including both the MB and their variants, which had potential significant values for predicting MGC. In conclusion, combined of assessing specific somatic variants and MB may be useful for predicting MGC development. This study included a limited number of subjects; however, our novel findings may encourage further exploration of the significance of the molecular features of EGC that predict MGC development, thereby promoting focused follow-up strategies and helping elucidate the mechanisms.

Risk factors for gastric metachronous lesions after endoscopic or surgical resection: a systematic review and meta-analysis

“…Finally, gastric neutrophilic infiltration in the corpus [23], methylation level of miR-124a-3 gene [24], and somatic genomic alterations (RECQL4, JAK3 m, ARID1A, and MAGl1 genes) [25] were associated with MGC development in single studies.…”

“…According to the aforementioned search strategy and after removal of duplicates, a total of 889 studies were identified. After excluding irrelevant citations, 208 papers were assessed for full-text screening, of which 52 met inclusion/exclusion criteria and were included in the systematic review [6,7,9,10,12,13,[17][18][19][20][21][22][23][24][25][26]; plus references 1s-36 s in the online-only Supplementary material (▶ Fig. 1).…”

Gastric Xanthelasma, Microsatellite Instability and Methylation of Tumor Suppressor Genes in the Gastric Mucosa: Correlation and Comparison as a Predictive Marker for the Development of Synchronous/Metachronous Gastric Cancer

“…These results may be reasonable, as several studies have shown that MSI and/or hMLH1 methylation is not useful for prediction of the development of GC [ 9 , 40 ]. On the other hand, genetic researchers have continuously investigated and identified some candidate molecular markers (methylation of microRNA-34b/c and -124a3 or somatic mutation of ARID1A and MAGI1 ) for prediction of the development of metachronous GC [ 41 , 42 , 43 ]. However, since molecular alterations in GC patients are very complex and diverse [ 37 , 38 , 39 ], it might be difficult to select a specific genetic marker that can predict the development of synchronous/metachronous GCs.…”

MAGI1, a Scaffold Protein with Tumor Suppressive and Vascular Functions

“…Regarding MAGI1, a recent report revealed that MAGI1 mediates tumor metastasis through the c-Myb/miR-520h/MAGI1 signaling pathway in renal cell carcinoma [125]. Somatic genomic alterations of MAGI1 genes were also found to be associated with metachronous gastric cancer development [126], and in a DNA methylation analysis of anaplastic thyroid cancer (ATC), MAGI1 displayed promoter methylation as well as decreased expression in ATC compared with normal thyroid tissue [127]. Aberrant DNA methylation can result in both upregulation of oncogenes and the silencing of tumor suppressor genes [128].…”