Germline Mutations in MSR1, ASCC1, and CTHRC1 in Patients With Barrett Esophagus and Esophageal Adenocarcinoma

CONTEXT Barrett esophagus (BE) occurs in 1% to 10% of the general population and is believed to be the precursor of esophageal adenocarcinoma (EAC). The incidence of EAC has increased 350% in the last 3 decades without clear etiology. Finding predisposition genes may improve premorbid risk assessment, genetic counseling, and management. Genome-wide multiplatform approaches may lead to the identification of genes important in BE/EAC development. OBJECTIVE To identify risk alleles or mutated genes associated with BE/EAC. DESIGN, SETTING, AND PATIENTS Model-free linkage analyses of 21 concordant-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005-2006). Significant germline genomic regions in independent prospectively accrued series of 176 white patients with BE/EAC and 200 ancestry-matched controls (2007-2010) were validated and fine mapped. Integrating data from these significant genomic regions with somatic gene expression data from 19 BE/EAC tissues yielded 12 “priority” candidate genes for mutation analysis (2010). Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued validation series of 58 cases (2010). MAIN OUTCOME MEASURES Identification of germline mutations in genes associated with BE/EAC cases. Functional interrogation of the most commonly mutated gene. RESULTS Three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC (all P