Methylated MDGA2: a new prognostic gastric cancer biomarker?

Last Updated: 2015-08-06

By Lorraine L. Janeczko

NEW YORK (Reuters Health) - Methylated MDGA2 detection may be a new biomarker for gastric cancer prognosis, new research from Hong Kong suggests.

"Our findings indicate that MDGA2 hypermethylation predicts poor prognosis in patients with gastric cancer, especially in the early stages," Dr. Jun Yu, of the Department of Medicine and Therapeutics of the Chinese University of Hong Kong, told Reuters Health by email.

"MDGA2 acts as a novel tumor suppressor and is frequently silenced or down-regulated in gastric cancer by promoter hypermethylation. MDGA2 methylation is significantly associated with reduced disease-free survival in patients with gastric cancer and thus may serve as a new biomarker for gastric cancer prognosis," Dr. Yu wrote.

"Our findings surprised us. MDGA2 belongs to the brain-derived immunoglobulin superfamily and has been found to regulate axon growth and inhibitory synapse development. Human MDGA2 expression occurs in the normal human stomach. Our study showing that MDGA2 acts as a novel tumor suppressor is the first to explain the functional significance and molecular mechanism of MDGA2 in gastric cancer," he added.

Using promoter methylation assay, Dr. Yu and colleagues showed that MDGA2 (meprin, A-5 protein, receptor protein-tyrosine phosphatase mu domain containing glycosylphosphatidylinositol anchor 2) is preferentially methylated in gastric cancer. They reported their results July 23 in the journal Gut.

The researchers evaluated MDGA2 methylation status by combined bisulfite restriction analysis and bisulfite genomic sequencing and they determined the effects of MDGA2 re-expression or knockdown on cell proliferation, apoptosis, and the cell cycle.

They identified MDGA2 interacting protein by mass spectrometry and MDGA2-related cancer pathways by reporter activity and polymerase chain reaction array analyses; and they assessed the clinical impact of MDGA2 in 218 patients with gastric cancer.

The authors found that MDGA2 suppressed tumors by cooperating with DNA methyltransferase 1 associated protein 1 (DMAP1) to activate the p53/p21 signaling cascade.

They detected MDGA2 promoter methylation in 62.4% of gastric cancers (136 of 218).

Patients with MDGA2 hypermethylation had significantly decreased survival according to multivariate analysis (p=0.005), and MDGA2 hypermethylation was significantly associated with shortened survival in patients with early gastric cancer in Kaplan-Meier survival curves (p<0.05).

"Globally, gastric cancer is the fifth-leading cause of cancer and the third-leading cause of cancer-related mortality. The prognosis of patients with gastric cancer continues to be poor, despite improving surgical and adjuvant treatment approaches, with a five-year overall survival less than 25%," Dr. Yu said.

"Identifying novel tumor suppressive genes targeted by promoter hypermethylation in gastric cancer may provide insights into the epigenetic mechanisms for the inactivation of tumor suppressive pathways. This is also important for identifying new markers and therapeutic targets for the diagnosis and treatment of this disease," he said.

Dr. Jose Mario Pimiento, of the Moffitt Cancer Center in Tampa, Florida, told Reuters Health by email that these findings, while interesting, are not surprising, and that many molecules may act as tumor suppressors in various oncologic processes.

Dr. Pimiento, who was not involved in the study, added that it "is important as part of the global effort to find biomarkers and potential targets for novel therapies in cancers, such as gastric, esophageal and pancreatic, which traditionally have had dismal outcomes."

"This study is very preliminary as its results are mostly based on cell lines; the clinical data are difficult to apply to a western population as we use the chemotherapy-first approach for many patients starting with stage II and above cancers, a practice different from the standard of care in China, where the surgery-first approach is followed by chemotherapy. So it is not clear how these results will be affected by giving therapy first," he cautioned.

"Therefore, at this moment, the results will not have any impact on patient care, especially in western populations. Even if these results are replicated, many more clinical studies need to be conducted to confirm clinical relevance," he advised.

Dr. Yu agreed that further study is needed. "How MDGA2 can help in the therapy of gastric cancer remains unclear. We will investigate if it is a therapeutic target for gastric cancer," he said.

The authors reported no disclosures.

SOURCE: http://bit.ly/1P94RqW

Gut 2015.