The hypermethylation of EDNRB gene was remarkably related to infiltration and metastasis of gastric cancer and may attribute to the tumor progression. EDNRB is a new candidate tumor suppressor gene which is often down-regulated or even silenced by promoter hypermethylation in various human cancers. Low EDNRB expression played a role in the progression of ACC tumors. The autosomal recessive mutation in EDNRB may underlie a part of WS1 with the current diagnostic criteria, and supported that Hirschsprung's disease is a multifactorial genetic disease which requires additional factors.