Somatostatin Methylation as a Biomarker for Gastric Cancer: Ready for “Prime Time” or for Further Validation?

Gastric cancer remains the fourth leading cancer in worldwide incidence, and the second leading cause of cancer-related death. Therefore, it continues to be a global healthcare problem. Infection with Helicobacter pylori (H. pylori), a class one carcinogen according to the World Health Organization classification, is believed to be one of the major underlying risk factors for this disease. Nonetheless, other risk factors such as high-salt diet, lack of fruit intake and genetics of the host and H. pylori are all factors that interplay together to dictate the outcome in a population. This complexity continues to challenge our understanding of the biology of this devastating cancer [1, 2]. Over the past few decades, there has been a steady decline in the incidence of H. pylori infection in the United States and many Western countries. Notably, as this trend continues, there has been a significant decline in the overall incidence of noncardia gastric cancer. In the last decade, tremendous gains have been made for a better understanding of the molecular basis underlying the neoplastic transformation of the gastric epithelial cells; however, the precise molecular mechanisms operational in this disease still remain elusive. Nonetheless, in light of current epidemiological and scientific evidence, there is a general consensus that gastric carcinogenesis is a multistep process that requires equal participation of not only genetic events, but frequent involvement of epigenetic alterations as well. Epigenetic refers to modifications of the genome heritable during cell division that do not involve changes in the DNA sequence. Epigenetic mechanisms act to change the accessibility of the chromatin to transcriptional regulation via modifications of the DNA and by modification or re-arrangement of the nucleosomes. The role of epigenetic mechanisms, in particular DNA methylation of CpG dinucleotides within promoter regions of genes, in regulating the expression of genes has gained considerable attention in the past few years [3]. Promoter DNA methylation offers an alternative mechanism for silencing gene expression, irrespective of the DNA copy numbers or the mutational status of the gene [4, 5]. From a molecular standpoint, CpG island methylation is viewed to provide the obligatory ‘‘second hit’’ in the Knudson’s two-hit hypothesis to inactivate the normal allele of a tumor suppressor gene. Growing evidence suggests that aberrant DNA methylation is a critical mechanism for tumor suppressor gene inactivation in most human cancers [5]. Promoter hypermethylation has been associated with a wide variety of genes, including genes involved in cell proliferation, cell cycle, apoptosis, angiogenesis, DNA repair and metastasis. Apparently, hypermethylation-associated gene silencing provides cancer cells with a growth advantage similar to deletions and mutations. Given the unprecedented interest in identifying the molecular basis of human cancers, data on the list of hypermethylated genes in different cancers are progressively increasing. In this issue of Digestive Diseases and Sciences, Jackson and colleagues [6] provide interesting new findings involving aberrant DNA methylation, specifically methylation of somatostatin (SST), in gastric adenocarcinoma. In this study, the authors have used state-of-the-art methodologies and demonstrated that the SST transcripts are down-regulated in 93% of gastric carcinoma samples (30 of 32 cases). Next, in their quest to understand the molecular mechanism for the abrogated SST expression in A. Goel (&) Gastrointestinal Cancer Research Laboratory, Baylor University Medical Center, 3500 Gaston Avenue, Suite 250 Hoblitzelle, Dallas, TX 75246, USA e-mail: ajayg@baylorhealth.edu