Germline variant in MSX1 identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma.

The vast majority of esophageal adenocarcinoma cases are sporadic and caused by somatic mutations. However, over the last decades several families have been identified with clustering of Barrett's esophagus and esophageal adenocarcinoma. This observation suggests that one or more hereditary factors may play a role in the initiation of Barrett's esophagus and esophageal adenocarcinoma in these families. A Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma was identified. Normal DNA obtained from the proband diagnosed with Barrett's esophagus was analyzed with SNP array and exome sequencing. A custom-made panel consisting of potential germline variants was verified in the normal DNA of the affected family members. In addition, the respective tumors were analyzed for somatic loss of the wild type allele or the presence of an inactivating somatic mutation in the wild type allele. Exome sequencing revealed 244 candidate variants in the normal DNA of the proband, of which 212 variants were verified successfully. After the normal DNA of the affected family members was analyzed for the presence of the 212 potential germline variants and subsequently the respective tumors, only one potential germline variant in MSX1 (chr4: 4861985 T > G, c.359T > G, p.V120G, NM_002448) showed loss of the wild type allele in the tumor DNAs of the affected family members. A germline variant in MSX1 was identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma. This finding indicates that the germline defect in MSX1 may be associated with Barrett's esophagus and cancer in this particular family.