Gallbladder cancer progression and its relationship to E- c adherin , CDKN2A ( cyclin-dependent kinase inhibitor 2A p16), REPRIMO (TP53 dependent G2 arrest mediator candidate) and UCHL1 (ubiquitin carboxyl-terminal esterase L1) methylation status . The metaplasia frequently appears as an adaptive process to chronic inflammation generally produced by a gallstone. Dysplasia appears on top of this metaplasia, which progresses to a carcinoma in situ and subsequently becomes invasive. The progression of gallbladder cancer is accompanied by aberrant methylation of multiple genes and global hypomethylation. The first horizontal pyramid represents the decreasing methylation level in specific genes with oncogenic properties (UCHL1) that exhibits a methylated promoter region in normal cells, which can become activated in cancer cells by the loss of its methylation. Therefore, this pyramid shows the loss of global methylation and of this specific gene as the lesion progresses. The second horizontal pyramid represent methylation gain as the lesion progress; many tumor suppressor genes are silenced by DNA methylation during carcinogenesis (E-cadherin CDKN2A REPRIMO). Modified from "Preneoplastic lesions of a gallbladder from morphological and molecular points of view" 2007 . With permission from Nova Science Publishers, Inc.