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Significance Familial esophageal squamous cell carcinoma (ESCC) often shows early onset and worse prognosis. Little is known about the genetic basis underlying the pathogenesis of familial ESCC. To identify the genetic alterations associated with familial ESCC susceptibility, we compared the gene-expression profiles of familial and sporadic ESCCs. We found that A-to-I RNA editing–mediated downregulation ofSLC22A3 is almost exclusively present in familial ESCC and may serve as a potential biomarker for familial ESCC patients. Molecular mechanism study further revealed that a single mutation at the RNA level could change the protein structure of SLC22A3, leading to a loss of inhibitory capability for the metastasis-promoting protein ACTN4. Our findings provide insights that may lead to more effective clinical management of individuals at high risk of familial ESCC withSLC22A3 deregulation.

RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer