DNA hypomethylation-related overexpression of SFN, GORASP2 and ZYG11A is a novel prognostic biomarker for early stage lung adenocarcinoma

Abstract

Although alteration of DNA methylation in advanced cancer has been extensively investigated, few data for early-stage lung adenocarcinoma are available. Here, we compared DNA methylation profiles between adenocarcinoma in situ (AIS) and early invasive adenocarcinoma using the Infinium methylation array to investigate methylation abnormalities causing early progression of adenocarcinomas. We focused on differentially methylated sites which were located in promoter CpG islands or shore regions, and identified 579 hypermethylated sites and 23 hypomethylated sites in early invasive adenocarcinoma relative to AIS and normal lung. These hypermethylated genes were significantly associated with neuronal pathways such as the GABA receptor and serotonin signaling pathways. Among the hypomethylated genes, we found that GORASP2, ZYG11A, and SFN had significantly lower methylation rates at the shore regions and significantly higher protein expression in invasive adenocarcinoma. Moreover, overexpression of those proteins was strongly associated with patient’s poor outcome. Despite DNA demethylation at the promoter region might be rare relative to DNA hypermethylation, we identified 2 new genes, GORASP2 and ZYG11A, which show hypomethylation and overexpression in invasive adenocarcinoma, suggesting that they have important functions in tumor cells. These genes may be clinically applicable as prognostic indicators and could be potential novel target molecules for drug development.

Carcinogen‐induced tumors in SFN‐transgenic mice harbor a characteristic mutation spectrum of human lung adenocarcinoma

“…Previously, we examined the gene expression profiles of early stage lung adenocarcinomas and identified stratifin (SFN, 14‐3‐3 sigma), which showed significantly higher expression in small but invasive lung adenocarcinoma (tumor size less than 3 cm in diameter) than in adenocarcinoma in situ or normal lung . Overexpression of SFN is due to DNA hypomethylation in its promoter region and is associated with poor patient outcome in lung adenocarcinoma . We have found that suppression of SFN reduces cell proliferation in vitro and tumor formation or metastasis in vivo, suggesting that SFN facilitates tumor progression.…”

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

“…Additional functional validation in sex-stratified models will be needed to test the gender specific roles of ZYG11A variants. High levels of ZYG11A are associated with advanced lung adenocarcinoma and drives cellular proliferation in part via upregulation of cyclin E to promote tumorigenesis (Husni et al, 2019;Wang et al, 2016). Recent studies implicated ZYG11A as downstream of the IGF-1 pathway in p53 wild-type cancer cells (Achlaug et al, 2019).…”

MicroRNAs in Lung Cancer Oncogenesis and Tumor Suppression: How it Can Improve the Clinical Practice?

“…The hypomethylation mechanisms include disruption and loss of DNA methylation affecting genomic integrity and stability [ 4 ]. Some genes, such as GORASP2, ZYG11A, and SFN, are significantly hypomethylated in LC adenocarcinoma [ 9 ].…”

“…Most of the LC are related to DNA hypermethylation, however, some genes (GORASP2 and ZYG11A) are hypomethylated and overexpressed in invasive adenocarcinoma. Thus, there is a large field for the development of new prognostic indicators and potential novel target molecules for clinical applications [ 9 ].…”