DNA promoter methylation as a diagnostic and therapeutic biomarker in gallbladder cancer

Several studies mention the possible role of DNA methylation in gallbladder carcinogenesis. This epigenetic modification affects tumor suppressor genes involved in regulation pathways, cell cycle control, cell adhesion and extracellular matrix degradation, in a sequential and cumulative way. Determining DNA methylation patterns would allow them to be used as biomarkers for the early detection, diagnosis, prognosis and/or therapeutic selection in gallbladder cancer.Gallbladder cancer (GBC) is the most frequent malignant tumor of the biliary tract and the fifth most common cancer of the digestive tract. The presenting symptoms are vague, so diagnosis commonly occurs at an advanced stage. This late diagnosis combined with the fact that the gallbladder lacks a serosa result in a rather dismal prognosis [1-3]. The highest GBC incidence rates have been reported in women from India (21.5 out of 100,000), Chile (18.1 out of 100,000), Pakistan (13.8 out of 100,000) and Ecuador (12.9 out of 100,000). High incidences have also been found in Korea and Japan and some central and eastern European countries such as Poland, the Czech Republic and Slovakia [4]. These facts suggest significant genetic-environmental influences in the development of the disease [5].Several factors have been associated with the risk of developing GBC. Lithiasis is one of the main risk factors, presenting in 65% to 90% of cases of GBC [2,3,6,7]; the risk is also associated with the number and size of the stones [8]. Likewise, and closely connected with lithiasis, chronic gallbladder inflammation might induce the continuous release of inflammatory mediators and growth factors (tumor promoters), which exert their effect on an epithelium previously damaged by carcinogenic agents [9]. Gallbladder cancer has also been associated with multiple familial polyposis (Gardner syndrome), Peutz-Jeghers syndrome, ‘porcelain’ gallbladder and anomalous pancreatobiliary ductal union [7].Adenocarcinoma is the most frequen