Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability

Abstract

BackgroundThe gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis.ResultsIn the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers.ConclusionsDefect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0096-y) contains supplementary material, which is available to authorized users.

Genetic association of deleted in colorectal carcinoma variants with breast cancer risk: A case-control study

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Netrin-1 in cancer: Potential biomarker and therapeutic target?

“…5,12,37,38 Two other studies also showed loss of expression of these receptors by methylation in gastric cancer. 39,40 However, the expression levels of Netrin-1 were not measured and compared with the expression levels of the receptors. Therefore, further preclinical and clinical studies are needed to address the significance of Netrin-1 as a biomarker in cancer.…”

Phosphoproteome Analysis Reveals Dynamic Heat Shock Protein 27 Phosphorylation in Tanshinone IIA-Induced Cell Death

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“…1 Gastric cancer is more common in Asia than in the rest of the world and is especially common in China and Japan. 2 The type of gastric cancer with the highest incidence is adenocarcinoma. 3 Previous studies have indicated that current therapies for gastric cancer involve combining several strategies, including surgery, chemotherapy, and radiation.…”